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6.7: Development of Blood Vessels and Fetal Circulation - Biology

6.7: Development of Blood Vessels and Fetal Circulation - Biology



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Learning Objectives

By the end of this section, you will be able to:

  • Describe the development of blood vessels
  • Describe the fetal circulation

In a developing embryo,the heart has developed enough by day 21 post-fertilization to begin beating. Circulation patterns are clearly established by the fourth week of embryonic life. It is critical to the survival of the developing human that the circulatory system forms early to supply the growing tissue with nutrients and gases, and to remove waste products. Blood cells and vessel production in structures outside the embryo proper called the yolk sac, chorion, and connecting stalk begin about 15 to 16 days following fertilization. Development of these circulatory elements within the embryo itself begins approximately 2 days later. You will learn more about the formation and function of these early structures when you study the chapter on development. During those first few weeks, blood vessels begin to form from the embryonic mesoderm. The precursor cells are known as hemangioblasts. These in turn differentiate into angioblasts, which give rise to the blood vessels and pluripotent stem cells, which differentiate into the formed elements of blood. (Seek additional content for more detail on fetal development and circulation.) Together, these cells form masses known as blood islands scattered throughout the embryonic disc. Spaces appear on the blood islands that develop into vessel lumens. The endothelial lining of the vessels arise from the angioblasts within these islands. Surrounding mesenchymal cells give rise to the smooth muscle and connective tissue layers of the vessels. While the vessels are developing, the pluripotent stem cells begin to form the blood.

Vascular tubes also develop on the blood islands, and they eventually connect to one another as well as to the developing, tubular heart. Thus, the developmental pattern, rather than beginning from the formation of one central vessel and spreading outward, occurs in many regions simultaneously with vessels later joining together. This angiogenesis—the creation of new blood vessels from existing ones—continues as needed throughout life as we grow and develop.

Blood vessel development often follows the same pattern as nerve development and travels to the same target tissues and organs. This occurs because the many factors directing growth of nerves also stimulate blood vessels to follow a similar pattern. Whether a given vessel develops into an artery or a vein is dependent upon local concentrations of signaling proteins.

As the embryo grows within the mother’s uterus, its requirements for nutrients and gas exchange also grow. The placenta—a circulatory organ unique to pregnancy—develops jointly from the embryo and uterine wall structures to fill this need. Emerging from the placenta is the umbilical vein, which carries oxygen-rich blood from the mother to the fetal inferior vena cava via the ductus venosus to the heart that pumps it into fetal circulation. Two umbilical arteries carry oxygen-depleted fetal blood, including wastes and carbon dioxide, to the placenta. Remnants of the umbilical arteries remain in the adult. (Seek additional content for more information on the role of the placenta in fetal circulation.)

There are three major shunts—alternate paths for blood flow—found in the circulatory system of the fetus. Two of these shunts divert blood from the pulmonary to the systemic circuit, whereas the third connects the umbilical vein to the inferior vena cava. The first two shunts are critical during fetal life, when the lungs are compressed, filled with amniotic fluid, and nonfunctional, and gas exchange is provided by the placenta. These shunts close shortly after birth, however, when the newborn begins to breathe. The third shunt persists a bit longer but becomes nonfunctional once the umbilical cord is severed. The three shunts are as follows:

  • The foramen ovale is an opening in the interatrial septum that allows blood to flow from the right atrium to the left atrium. A valve associated with this opening prevents backflow of blood during the fetal period. As the newborn begins to breathe and blood pressure in the atria increases, this shunt closes. The fossa ovalis remains in the interatrial septum after birth, marking the location of the former foramen ovale.
  • The ductus arteriosus is a short, muscular vessel that connects the pulmonary trunk to the aorta. Most of the blood pumped from the right ventricle into the pulmonary trunk is thereby diverted into the aorta. Only enough blood reaches the fetal lungs to maintain the developing lung tissue. When the newborn takes the first breath, pressure within the lungs drops dramatically, and both the lungs and the pulmonary vessels expand. As the amount of oxygen increases, the smooth muscles in the wall of the ductus arteriosus constrict, sealing off the passage. Eventually, the muscular and endothelial components of the ductus arteriosus degenerate, leaving only the connective tissue component of the ligamentum arteriosum.
  • The ductus venosus is a temporary blood vessel that branches from the umbilical vein, allowing much of the freshly oxygenated blood from the placenta—the organ of gas exchange between the mother and fetus—to bypass the fetal liver and go directly to the fetal heart. The ductus venosus closes slowly during the first weeks of infancy and degenerates to become the ligamentum venosum.

Chapter Review

Blood vessels begin to form from the embryonic mesoderm. The precursor hemangioblasts differentiate into angioblasts, which give rise to the blood vessels and pluripotent stem cells that differentiate into the formed elements of the blood. Together, these cells form blood islands scattered throughout the embryo. Extensions known as vascular tubes eventually connect the vascular network. As the embryo grows within the mother’s womb, the placenta develops to supply blood rich in oxygen and nutrients via the umbilical vein and to remove wastes in oxygen-depleted blood via the umbilical arteries. Three major shunts found in the fetus are the foramen ovale and ductus arteriosus, which divert blood from the pulmonary to the systemic circuit, and the ductus venosus, which carries freshly oxygenated blood high in nutrients to the fetal heart.

Self Check

Answer the question(s) below to see how well you understand the topics covered in the previous section.

Critical Thinking Questions

  1. All tissues, including malignant tumors, need a blood supply. Explain why drugs called angiogenesis inhibitors would be used in cancer treatment.
  2. Explain the location and importance of the ductus arteriosus in fetal circulation.

[reveal-answer q=”863824″]Show Answers[/reveal-answer]
[hidden-answer a=”863824″]

  1. Angiogenesis inhibitors are drugs that inhibit the growth of new blood vessels. They can impede the growth of tumors by limiting their blood supply and therefore their access to gas and nutrient exchange.
  2. The ductus arteriosus is a blood vessel that provides a passageway between the pulmonary trunk and the aorta during fetal life. Most blood ejected from the fetus’ right ventricle and entering the pulmonary trunk is diverted through this structure into the fetal aorta, thus bypassing the fetal lungs.

[/hidden-answer]

Glossary

angioblasts: stem cells that give rise to blood vessels

angiogenesis: development of new blood vessels from existing vessels

blood islands: masses of developing blood vessels and formed elements from mesodermal cells scattered throughout the embryonic disc

ductus arteriosus: shunt in the fetal pulmonary trunk that diverts oxygenated blood back to the aorta

ductus venosus: shunt that causes oxygenated blood to bypass the fetal liver on its way to the inferior vena cava

foramen ovale: shunt that directly connects the right and left atria and helps to divert oxygenated blood from the fetal pulmonary circuit

hemangioblasts: embryonic stem cells that appear in the mesoderm and give rise to both angioblasts and pluripotent stem cells

umbilical arteries: pair of vessels that runs within the umbilical cord and carries fetal blood low in oxygen and high in waste to the placenta for exchange with maternal blood

umbilical vein: single vessel that originates in the placenta and runs within the umbilical cord, carrying oxygen- and nutrient-rich blood to the fetal heart

vascular tubes: rudimentary blood vessels in a developing fetus


As the fetus develops within the womb, fetal circulation is established during the early stages of development, allowing the growing fetus to receive the required oxygen and nutrients as well as dispose of waste products. This type of circulation refers to the circulatory system of a fetus which differs from postnatal circulation.

Fetal circulation, unlike postnatal circulation, involves the umbilical cord and placental blood vessels which carry fetal blood between the fetus and the placenta. It is usually established in the fetal period of development and is designed to serve prenatal nutritional needs, as well as permit the switch to a neonatal circulatory pattern at birth. Good respiration in the neonate depends on normal circulatory changes occurring at birth (transitional circulation), which results in oxygenation of the blood in the lungs when fetal blood flow through the placenta ceases.

Prenatally, the lungs do not provide gas exchange and the pulmonary vessels are vasoconstricted. Instead, the placenta acts as the gas exchange unit to oxygenate fetal blood. The three vascular structures most important in the transitional circulation are the ductus venosus, foramen ovale, and ductus arteriosus.


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Development and Cell Biology of the Blood-Brain Barrier

The vertebrate vasculature displays high organotypic specialization, with the structure and function of blood vessels catering to the specific needs of each tissue. A unique feature of the central nervous system (CNS) vasculature is the blood-brain barrier (BBB). The BBB regulates substance influx and efflux to maintain a homeostatic environment for proper brain function. Here, we review the development and cell biology of the BBB, focusing on the cellular and molecular regulation of barrier formation and the maintenance of the BBB through adulthood. We summarize unique features of CNS endothelial cells and highlight recent progress in and general principles of barrier regulation. Finally, we illustrate why a mechanistic understanding of the development and maintenance of the BBB could provide novel therapeutic opportunities for CNS drug delivery.

Keywords: astrocytes blood-brain barrier central nervous system endothelial cells neurovascular unit pericytes.


DISCUSSION

The existence of a common precursor for endothelial and hematopoietic cells, the hemangioblast, has been hypothesized for many years (Sabin, 1917 Murray, 1932) and recent studies have demonstrated they are present intra- and extra-embryonically in mouse (Ogawa et al., 2001 Orkin and Zon, 2002 Ueno and Weissman, 2006). Recently, Sequeira Lopez and associates reported simultaneous generation of endothelial and hematopoietic cells in several tissues of the mouse embryo and applied the term hemo-vasculogenesis to the process (Sequeira Lopez et al., 2003). The current study suggests that hemangioblasts are present intra-embryonically in developing choroid and documents apparent hemo-vasculogenesis in embryonic human choroid using Wright’s Giemsa staining and immunolocalization of Hb-∈ in the same cells that are positive for CD31, CD34, VEGFR-2, and vWf, standard markers for endothelial cells in adult tissue. However, CD31, CD34, and VEGFR-2 have been used as markers for hematopoietic precursors and VEGFR-2 is a marker for hemangioblasts (Forrai and Robb, 2003), while vWF is almost a definitive marker for endothelial cells, since the only other cell type expressing it is megakaryocytes. It was striking that a few cells were expressing Hb-∈, CD34, and vWf, further suggesting the same precursors were capable of erythropoiesis, hematopoiesis, and vasculogenesis, the definition of hemo-vasculogenesis. In the fetal period, hemo-vasculogenesis was complete and new blood vessels appeared to form by angiogenesis since endothelial cells were proliferating. However, there were free CD39 + cells present in choroid at the level of the choriocapillaris ( Fig. 10 ), so it is possible that these cells participate in vasculogenesis, which expands the vasculature to achieve adult vascular density as the eye enlarges.

Choroidal Vascular Development With Age

Prior studies of the choroid in human embryos and fetuses defined the anatomical events resulting in a choroidal vasculature. Ida Mann described the choriocapillaris as endothelial tubes and said that fetal erythrocytes were present (Mann, 1928). Her drawings, however, do not clearly depict the erythrocytes inside of tubes. The ultrastructural study of Sellheyer and Spitznas clearly show erythroblasts, mesenchymal cells, and endothelial cells at 6.5 WG (Sellheyer, 1990). Only slit-like lumens were present and the 𠇎ndothelial cells” were very large and highly vesiculated. Mann (1928), Sellheyer and Spitznas (1988), and Heimann (1972), who used latex casts, observed only a choriocapillaris until around the end of the 8th WG. However, our study suggests that the lumens Mann reported may not have been endothelial tubes but rather hollow aggregates or islands of precursors, which were shown by serial sectioning in the current study to not be connected to patent blood vessels. Furthermore, the erythrocytes were actually erythroblasts forming in those islands of cells. At 12 WG, the prior studies observed large and intermediate blood vessels in choroid (Mann, 1928 Heimann, 1972 Sellheyer and Spitznas, 1988). So our anatomical results are consistent with the prior observations but the previous studies do not definitively identify the cells involved, their relationship to vascular precursors, or the mechanism by which the vessels assemble.

Choriocapillaris Forms by Hemo-Vasculogenesis

The first time points examined in the current study were 5.5 WG, when sheets of CD39+ cells were present in a flat mount ( Fig. 9A ), and 6 WG when the sheet of cells was labeled with vascular markers (CD31, CD34, CD39, and VEGFR-2) in cross-sections of developing choriocapillaris ( Fig. 3A𠄽 ). It was striking in specimens embedded in JB-4 that the sheet contained cells that had extremely acidophilic cytoplasm as observed in erythroblasts, which are present in the embryo at this stage. We observed many nucleated erythroblasts surrounded by loosely arranged apparent endothelial cells of the choriocapillaris. Recently, Sequira Lopez and associates provided evidence that erythroblasts and endothelial cells are generated simultaneously and likely derived from common precursor cells in mouse embryo (Sequeira Lopez et al., 2003) but their analysis did not prove the origin of both cell types was clonal. The precursors (VEGFR-2 + ) aggregate, then differentiate into erythroblasts and endothelial cells. Once the lumens form, erythroblasts are separated from endothelial cells and could be observed in the newly formed lumens. Furthermore, they demonstrated that this phenomenon occurs throughout the mouse embryo and they called this process hemo-vasculogenesis, the process by which vasculogenesis, erythropoiesis, and hematopoiesis occur simultaneously in island-like structures and perhaps from common precursors.

There are several lines of evidence that suggest that the embryonic human choriocapillaris forms by hemo-vasculogenesis. First, in JB-4 serial sections in the current study, island of precursors were observed, which were not associated with formed blood vessels when the tissue was serially sectioned. Cells in these islands appeared to be erythroblasts with Giemsa staining they had large nuclei with acidophilic cytoplasm. Furthermore, they were both in cavities made within the islands and, in other examples, they formed the walls of the cavities i.e., they were not always in the presumptive lumen. In fact, individual erythroblasts were observed in choroidal stroma as well. Confirmation that these cells were erythroblasts was achieved by double staining with endothelial cell markers, hematopoietic cell markers, and Hb-∈. Hb-∈ is one of the chains of embryonic hemoglobin and has been used recently to demonstrate erythroblast differentiation in embryoid bodies formed from embryonic stem cells in vitro (Zambidis et al., 2005). Double labeling with vascular markers (CD31, CD34, and VEGFR-2) and Hb-∈ demonstrated that cells within the islands of precursors where choriocapillaris was forming and even some single cells in choroidal stroma were double labeled between 6 and 7 WG. The fact that they had Hb-∈, endothelial cell, and hematopoietic markers of varying degree suggests that endothelial cells, erythropoietic cells, and hematopoietic cells in the initial choriocapillaris may have common precursors, i.e., hemo-vasculogenesis appears to be the way by which the initial choriocapillaris develops. One difference between the current observations on human embryonic choriocapillaris and the prior study in mouse by Sequira Lopez is that they never observed erythroblasts forming the wall of the cavities nor did they observe vesicles or vacuoles inside the clusters of erythroblasts ( Fig. 2 ). Sequira Lopez found that mouse erythroblasts were generated after lumens or cavities were formed (Sequeira Lopez et al., 2003). This was similar to the Florence Sabin’s description of blood islands in yolk sac, hematopoietic cells in the center, and endothelial cells forming the lumen (Sabin, 1917). However, Ferkowicz and Yoder have found that primitive erythropoiesis is initiated extra-vascularly (Ferkowicz and Yoder, 2005). In the study of Zambidis et al. (2005) on human embryoid bodies, they found erythroblasts make hollow chambers as we observed in choroid, as well as develop within endothelial cell–lined chambers.

Angiogenesis Involved in Large Choroidal Blood Vessel Development

A few large vessels were already forming in the posterior pole at the same embryonic time points as choriocapillaris. Those vessels had packed erythroblasts in their lumens, like the forming choriocapillaris, and were free-standing structures. Therefore, some arteries and veins may develop by the same process as choriocapillaris, hemo-vasculogenesis (results not shown). The number of those vessels was not nearly enough to form all of the large and intermediate choroidal blood vessels found in adult. Ki67 + cells seemed to be associated with the development of intermediate and large choroidal vessels as development progressed. To confirm whether endothelial cells were proliferating, double staining for CD34 and Ki67 was done on older specimens and it was apparent that endothelial cells were proliferating, especially on the scleral side of choriocapillaris and at the tips of diving vessels at 12 WG and older ( Fig. 7C,D ). Our results showed more proliferating cells are in the posterior pole than in the periphery. The progression of intermediate and large vessel formation suggested that the deeper larger blood vessels developed centrifugally from the optic nerve region. Since Ki67 expression was associated with endothelial cells at vessel tips, the development of most large choroidal vessels and perhaps anastomosis of choriocapillaris with large and intermediate choroidal blood vessels appears to be accomplished by angiogenesis. With age, the number of Ki67 + cells increased throughout the choriocapillaris and may represent angiogenesis that is required to increase the density of the choriocapillaris as the globe expands. The density of capillaries at 12 WG ( Fig. 10A ) is quite low compared to the adult choriocapillaris (McLeod and Lutty, 1994).

It is interesting that the fetal human retinal vasculature only forms after 12 WG. It forms by vasculogenesis, the differentiation and coalescence of CD39 + angioblasts without proliferation of the angioblasts (McLeod et al, 2006). The vascular markers employed in this study, CD34, CD31, and VWf, were only observed in endothelial cells in formed retinal blood vessels, and not associated with angioblasts. Therefore, the choroidal and retinal vasculatures in embryonic and fetal humans form by unique and different processes, which may help explain their distinct differences in the adult human.

In summary, islands or aggregates of precursors as found in yolk sac appear to be the origin of the first blood vessels in human embryonic choroid. This process, hemo-vasculogenesis, is responsible for formation of blood cells as well as endothelial cells from common precursors, as observed in embryoid bodies formed from human embryonic stem cells in vitro (Zambidis et al., 2005). This study is the first to suggest in human that hemangioblasts are present intra-embryonically and that they appear to be the common precursor that participates in hemo-vasculogenesis. This in situ assembly of choriocapillaris explains how the choriocapillaris can form without any apparent feeding arterioles or draining venules. The lobular pattern of adult choriocapillaris may be a consequence of development from islands of precursors where capillaries are formed independent of flow and without guidance of neurons or matrix. This is as opposed to human retina where a mesh-like capillary system forms initially by vasculogenesis (Chan-Ling et al., 2004 McLeod et al., 2006) but it is remodeled in part by blood flow and in part by neuronal development and tissue needs, resulting in an end-arterial vasculature. There are free CD39 + cells, presumably angioblasts, present during fetal development that may contribute to expansion of the choriocapillaris by vasculogenesis. The choriocapillaris later appears to bud by angiogenesis forming anastomoses with intermediate and larger choroidal blood vessels. In the specimens used in this study, an adult density and pattern of choriocapillaris was never achieved, but the lobular system may not form completely until arterioles that feed the choriocapillaris and venules that drain this system are well established. The current study demonstrates for the first time the embryonic development of an ocular vasculature by hemo-vasculogenesis, which may contribute to the early development and unique attributes of the human choroidal vasculature, which is responsible for the development, health, and function of the retinal photoreceptors.


Abstract

The formation of new blood vessels in the adult organism not only contributes to the progression of diseases such as cancer and diabetic retinopathy but also can be promoted in therapeutic approaches to various ischemic pathologies. Because many of the signals important to blood vessel development during embryogenesis are recapitulated during adult blood vessel formation, much work has been performed to better-understand the molecular control of endothelial differentiation in the developing embryo. In this review, we describe the current understanding of where endothelial differentiation from pluripotent progenitor cells occurs during development, how this process is controlled at the molecular level, and what model systems can be used to investigate the earliest steps of blood vessel formation.

The formation of new blood vessels in the adult organism not only contributes to the progression of diseases such as cancer and diabetic retinopathy but also can be promoted in therapeutic approaches to various ischemic pathologies. In this review, we describe the current understanding of where endothelial differentiation from pluripotent progenitor cells occurs during development, how this process is controlled at the molecular level, and what model systems can be used to investigate the earliest steps of blood vessel formation.

Consistent with its central importance in embryonic development, the history of research into vascular development is populated with seminal histologists such as Wilhelm His and Florence Sabin. 1 Ideas about endothelial origin followed soon after the development of histology as a technique and cell biology as a field of study. Beyond characterization of the fundamental anatomy of vascular development (in many timeless analyses that bear rediscovery by present-day investigators), the first investigators in this field participated in one of the classic debates in all of developmental biology: where and when do endothelial cells (and hence blood vessels) arise in the developing embryo? Because blood vessels are first observed in the yolk sac in avian and mammalian embryos, it was initially assumed that all blood vessels arise from extraembryonic tissues. However, careful histological analysis subsequently indicated that isolated foci of endothelial cells can also be observed in the embryo proper, which suggested that blood vessels arise from an intraembryonic source (specifically, the mesoderm) rather than via colonization. The latter model has been successively reconfirmed by increasingly sophisticated approaches to isolate and track blood vessel development in mammalian systems (discussed below).

Gastrulation and Post-Gastrulation Events

Although there has been considerable debate about what is a surprisingly elusive question, it is now generally accepted that the mesoderm is the exclusive source of endothelial cell progenitors. Although efforts have been made to identify specific loci within the mesoderm that preferentially specify endothelial fates, it now seems clear that precursors to endothelium arise within all intraembryonic mesoderm, with the exception of the notochord and prechordal plate, as loose aggregations of cells bearing early markers of the endothelial lineage with the potential to coalesce into vascular cords. 2

The signals for induction of angioblasts (defined by Gray’s Anatomy as “individual vasoformative cells”) are not entirely clear. Initiation of vascular differentiation within the embryo occurs in opposition to endoderm, which suggests that endoderm-derived signals are required for angioblast commitment within mesoderm. 3 Several signals are appropriately expressed in a spatial and temporal pattern within the endoderm to fulfill this role and are required for normal vascular development. 4 However, recent evidence suggests that angioblast commitment is not totally dependent on endoderm-derived signals, although later morphogenetic steps in vascular development may require endoderm–mesoderm interactions. 5

The pluripotency of vascular precursors has also been a vexing issue within the field. The close colocalization of endothelial and hematopoietic precursors (so-called blood islands) within the yolk-sac has been recognized since early in the 20 th century. 6 This raised the possibility that both lineages arise from a common precursor, the hemangioblast. Subsequent studies have indicated that both lineages bear certain common molecular markers, and cells with the potential to produce either lineage have been isolated from differentiating mouse embryoid bodies. 7,8 The pluripotency of these putative hemangioblasts has not been completely characterized, although some data support the possibility that these multipotential cells may also assume characteristics of the smooth muscle lineage under appropriate inductive conditioning. 7 It also does not seem likely that hemangioblast identity is a required step for all endothelial development, and in fact direct differentiation of angioblasts from mesoderm is also a well-supported phenomenon. 9,10 The teleological rationale for direct endothelial differentiation from mesoderm under some circumstances rather than passage through a hemangioblast intermediary stage is not necessarily clear, but direct differentiation of endothelial cells appears to occur primarily within somites. 11 In addition, it has been suggested that in some cases hematopoietic cells may arise directly from differentiated endothelium—so-called hemogenic endothelium. 8,12,13

Despite data supporting the existence of the hemangioblast, definitive isolation of these cells and localization within the developing embryo has been an extraordinary challenge. However, recent evidence indicates that cells with hemangioblast properties are present transiently in the posterior segment of the primitive streak during gastrulation and are defined by the coexpression of the vascular endothelial growth factor receptor flk1 and the mesodermal T-box gene brachyury. 14,15 These data also suggest that endothelial and hematopoietic fates of embryonic cells are established before the appearance of yolk-sac blood islands during development. In fact, some data suggest that the hemangioblast lineage may be committed before gastrulation within the epiblast. 16 Despite this controversy, and for the sake of clarity, the term “hemangioblast” will be used throughout the remainder of this review to describe bipotential endothelial cell precursors.

Extraembryonic Vasculogenesis

Blood vessel formation is classically divided into 2 categories. Vasculogenesis refers to the in situ differentiation of endothelial cells to form blood vessels, with or without associated angioblast migration. In contrast, angiogenesis refers to the formation of new blood vessels via extension or remodeling of existing blood vessels. Angiogenesis occurs throughout development and in adulthood, whereas vasculogenesis is generally thought to occur during a limited period early in embryonic development. (The term “vasculogenesis” is occasionally used to refer to the development of blood vessels during adulthood, especially when associated with circulating vascular progenitor cells. However, given the distinct developmental mechanisms of each process, this seems to be an inappropriate use of this term based on its natural definition.) Vasculogenesis is further subdivided based on whether it occurs within the extraembryonic or intraembryonic compartments. The best available evidence suggests that these 2 waves of vasculogenesis are temporally and spatially distinct, and molecular studies indicate that they are also partially distinct at the mechanistic level.

Extraembryonic vasculogenesis precedes intraembryonic vascular development, and in mammals is first apparent as blood islands assembling within the mesodermal layer of the yolk sac (Figure). Blood islands are foci of hemangioblasts that differentiate in situ, forming a loose inner mass of embryonic hematopoietic precursors and an outer luminal layer of angioblasts. Blood islands eventually coalesce into a functional vascular network that constitutes the vitelline circulation, which is adapted to transfer nutrients from the yolk sac to the embryo proper. Recent evidence indicates that extraembryonic blood vessels may also arise independently of blood islands via direct differentiation of angioblasts from mesoderm. 9 Vessels arising via yolk sac vasculogenesis communicate with the fetal circulation via the vitelline vein, but otherwise do not contribute to intraembryonic vasculature.

Vasculogenic “hot-spots” in the mouse embryo. dpc, days post coitus YS, yolk sac (orange) Al, allantois (purple) PPS, posterior primitive streak (green) PE, pro-epicardium (red) AGM, aorto-gonad-mesonephros region PAS, para-aortic splanchnopleure.

De novo extraembryonic vasculogenesis also occurs in the allantois, a structure responsible for the induction of placental development and for the formation of the umbilical vessels. Avascular allantoides can be excised from the developing embryo and cultured in isolation for &1 day, during which time they develop a definitive vascular plexus. 17 This indicates that vasculogenesis can proceed independently in the allantois during development. Because of this, primitive vessels are already in place in the allantois as it makes contact with the chorion to facilitate the formation of the maternal–fetal circulation. Whether these cells also contribute to hematopoiesis and whether they receive inductive signals from endoderm or allantoic mesothelium is still undergoing debate, and may differ between species. 18–20 Furthermore, given the close proximity of the developing allantois to the yolk sac mesoderm and posterior primitive streak, 2 structures with potent hemangioblastic potential, further studies have sought to address the exact temporal and anatomic origins of the vasculogenic cells resident in the allantois. 21

Intraembryonic Vasculogenesis

Although recent evidence suggests that intraembryonic vasculogenesis can occur throughout most of the intraembryonic mesoderm, much work has been performed to characterize the different origins of particular vascular structures. As might be expected, the endocardium and great vessels are the first intraembryonic endothelial structures formed during development. 9 The endocardium originates in mammals from clusters of migrating angioblasts derived from presomitic cranial mesoderm that enter the pericardial area to form a vascular plexus adjacent to the developing myocardium. This plexus undergoes remodeling to form the endocardial tube, which is the first vascular structure formed in the mammalian embryo. 9 Simultaneous to heart development, vasculogenesis is initiated within the aortic primordia, a collection of mesoderm just lateral to the midline, to give rise to the dorsal aortae and the cardinal veins. 22 During this development, differentiating angioblasts assemble into primary vascular networks, which are then remodeled in a bidirectional fashion to generate the bilateral embryonic aortae. 9 This region, later termed the para-aortic splanchnopleure (PAS), and then the aorta-gonad-mesonephros (AGM) region, continues to be a “hot-spot” for hematovascular differentiation during development (Figure). 12

As the heart enlarges, passive diffusion of nutrients and waste becomes limiting, and a coronary vasculature is formed to supply the metabolically active heart tissue. Vascular precursor cells (including endothelial and smooth muscle cell progenitors) reside in the pro-epicardium (PE)—a mass of cells that appears to originate from splanchnic mesoderm in conjunction with the septum transversum just inferior to the heart. 23 This cell mass makes contact with the developing heart tube and quickly spreads over the entire heart. Once spread, these cells undergo epithelial-to-mesenchymal transformation (EMT), and invade the underlying mesoderm, where they then give rise to the capillaries, veins, and arteries of the coronary vasculature. 24 The development of the coronary circulation is clearly unique, and still requires investigation to determine the timing and molecular nature of the signals necessary to induce endothelial differentiation in the PE. 25,26

Molecular Regulation

The anatomic basis for vascular development in the embryo has been clarified through studies that have been performed over the past century. In contrast, the molecular underpinnings for endothelial cell differentiation have only become clear in the last decade. In addition to cell-specific genetic determinants of endothelial differentiation, soluble factors are released that influence the fate of multiple cell lineages. Gain- and loss-of-function studies have helped us identify some of the participants in vasculogenesis. Specifically, targeted gene inactivation studies have better-defined the molecular regulatory mechanisms underlying these processes (Table). In this section, we review briefly the inter-relationships among some of the identified steps important to endothelial differentiation.

Genetic Experiments Exhibiting Developmental Vascular Phenotypes (not exhaustive)

Initiation

Key to any inductive process in the embryo is the elaboration of signals that are integrated to mark the initiation of a developmental cascade. In the case of early events in endothelial differentiation, these cues must determine the spatial and temporal appearance of hemangioblasts from undifferentiated mesoderm, and also the further maturation and assembly of these precursors into nascent blood vessels. Of the well-defined signaling pathways, the best data indicate that crucial roles exist for members of the fibroblast growth factors (FGF) and bone morphogenetic proteins (BMP) growth factor families as proximal inductive cues for the hematovascular lineage. FGF appear to be key components required for hematovascular differentiation in differentiating embryonic stem cells. 27 Concurrent with FGF signaling, BMPs, specifically BMPs 2 and 4, signal through downstream Smad proteins to help modulate early vascular development as indicated by gene deletion experiments. 28–31 The potent effect of the endogenous endothelial BMP inhibitor BMPER in suppressing endothelial differentiation also highlights the importance of this signaling system in vasculogenesis. 32 In addition, Indian hedgehog is implicated as an endoderm-derived signal for vascular competence. 4 Definitive endoderm and mesoderm specification is also thought to be mediated in part by Brachyury or T, a transcriptional target of the Wnt signaling pathway. 33 Wnt signaling pathways are essential during gastrulation, specifying pattern formation, and regulating stem cell differentiation during mammalian development. 34–36 However, remarkably little is known about how these upstream factors interact to specify vascular identity of precursors. In addition, none of these signals has specificity for the vascular lineage.

The first secreted molecule with specificity for the endothelium during development is vascular endothelial growth factor (VEGF), and the role of VEGF family members in developmental and adult angiogenesis is now well-described. Mice lacking a single copy of the VEGF gene die early in development, indicating the critical role for this signaling pathway in vascular development. 37 Cells that respond to VEGF must first express its receptors, Flk1 and Flt1 (VEGFR2 and VEGFR1). This indicates that VEGF itself cannot be the most proximal signal for endothelial differentiation, and it is still not clear precisely when VEGF first participates in vascular specification. VEGF receptors were thought to be restricted to the endothelial and early hematopoietic lineages however, Flk1 + mesodermal progenitor cells were recently reported to contribute to muscle lineages, 38 although these data have not been confirmed by other investigators. VEGF also binds the semaphorin receptor, neuropilin-1 (NP1), with high affinity in a complex that reportedly enhances VEGF binding to Flk1. 39,40 Both of the neuropilin coreceptors (NP1 and NP2) are necessary for proper vessel and yolk sac development. 40 Flk1 also forms a complex with VE-cadherin, β-catenin, and PI3-K to intercede a VEGF-A survival signal through activation of the downstream messenger AKT, followed by a decrease in Bcl2-mediated apoptosis. 41 Interestingly, in addition to playing roles in endothelial anchoring and VEGF-mediated survival, the signaling molecule β-catenin also participates in the canonical Wnt pathway during embryogenesis. 42 Additionally, VEGF-A is expressed as multiple splice variants with varying abilities to bind heparin sulfate, producing freely diffusible VEGF-A isoforms as well as those that are retained in the extracellular matrix. 43 Signaling of multiple VEGF splice variants among multiple receptors and coreceptors makes it difficult to correlate cellular and molecular function in nonlinear cross-talking pathways.

VEGF/Flk1 Regulation

Several upstream factors have been shown to regulate VEGF and Flk1 expression. The transcription factor hypoxia-inducible factor 1(HIF-1) and its family members play crucial roles in sensing changes in tissue oxygen tension and stimulating gene expression changes that enhance blood vessel growth into hypoxic tissues during post-gastrulation development. 44 Additional factors such as specificity protein 1 act in concert to regulate VEGF transcription. 45 Evidence supports BMP signaling as a proximal stimulus for Flk1 expression, and at the transcriptional level there appears to be necessary roles for GATA family proteins as well as the homeodomain protein HoxB5 in upregulation of Flk1 during development. 46 Another layer of regulation in endothelial development is ascribed to the ETS family of transcriptional factors that direct downstream endothelial specific expression of Flk1, Flt1, the angiopoietin receptors, and MEF2C, a recently identified member of the MADS box superfamily of vascular developmental transcription factors. 47 A genetic mutation of an unknown gene, termed “cloche,” leads to Flk1 deficiency with a subsequent failure in vasculogenesis. 48,49 Although still incompletely characterized, upstream cues that initiate VEGF and Flk1 expression, and other regulators of endothelial differentiation, are likely participants in early specification of the vascular lineage.

Functional Markers of Endothelial Differentiation

Identified markers of endothelial cells are used to track their transition from the early stages of stem cell differentiation to the mature vessel, as well to distinguish them from other lineages, such as hematopoietic and smooth muscle. Not surprisingly, many of the molecules used to track endothelial identity are functionally important. The appearance of Flk1 expression is at the present time the earliest marker available for the endothelial lineage during development. 8,50,51 Flk1 is expressed early in endothelial and hematopoietic cells, and persists in mature endothelium but not mature hematopoietic lineages. This pattern suggests that Flk1 may be a marker for hemangioblasts during early development, and this is born out by studies that indicate that the coexpression of Flk1 with mesoderm-derived transcription factors Brachyury or Scl/Tal1 denotes hemangioblasts. 9,15 It is also important to note that because Flk1 is expressed by angioblasts as well as mature endothelial cells, it cannot be used solely to distinguish between different stages of endothelial cell differentiation. As the endothelial lineage progresses, the expression of brachyury followed by Scl/Tal1 are lost, whereas the Flk1 marker is retained. 52 Elimination of SCL/Tal1 expression arrests hematopoiesis, but allows for endothelial cell progression. 52,53 SCL/Tal1 and FGFR-1 are suggested to be linked in the segregation of hemangioblasts into hematopoietic and endothelial lineages. 52 The entire transcriptional program of the endothelial lineage is yet to be established, and this represents a major limitation in our understanding of how cell-autonomous mechanisms coordinate development of vascular cell lineages.

Combinations of endothelial specific markers including VE-cadherin, PECAM-1, Tie-1, Tie-2, Flk1, and Flt1 are commonly used to trace endothelial differentiation. 54 As might be expected, these markers also serve in functions vital to endothelial formation, remodeling, and maintenance. For example, VE-cadherin is expressed from the committed angioblast to the mature endothelial cell, but not in hematopoietic progenitor cells. VE-cadherin, an adhesive cell–cell recognition protein, participates in cell-sorting during vascular morphogenesis. With the ability to anchor to the cortical actin cytoskeleton via catenin proteins and vinculin, VE-cadherin offers junctional strength between endothelial cells. 41 Mice deficient for VE-cadherin fail to couple a VEGF-A/Flk1–dependent endothelial survival signal to β-catenin and PI3-K, resulting in early embryonic death caused by severe vascular defects. 41,54 PECAM-1 and Tie also function during endothelial differentiation with roles in adhesion and vascular network formation, respectively. 55 In fact, PECAM-1 is commonly used to trace endothelial morphological development (ie, sprouting vessels). 46,56 Although the fine points of their signal transduction pathways remain poorly understood, the function of markers used to identify endothelial cells and their progenitors have provided us a framework for reaching a more complete understanding of vasculogenesis.

Additional Regulatory Cues

Downstream of the early events, the cues required for blood vessels to assemble become better known, if also more complex. Among paracrine factors, the angiopoietin family members bind to the tyrosine kinase receptors Tie-1 and Tie-2, which are structurally similar to the VEGF receptors and play crucial roles in endothelial cell survival and remodeling of capillary plexi. 57 Platelet-derived growth factors are required for recruitment of pericytes and smooth muscle cells to invest developing arteries and establish vasomotor tone. 58 Several transcription factors are known to participate in vascular assembly including vascular endothelial zinc finger, 59 GATA proteins, 60 several members of the Krüppel-like family of zinc finger proteins, 61 and Ets proteins, 62,63 which have all been linked to steps in endothelial cell differentiation by virtue of their cellular phenotypes of defined transcriptional targets. Homeodomain proteins such as HoxB3 and HoxD3 participate in morphogenetic events responsible for vascular tube formation. 64 Egfl7, a recently identified secreted factor in endothelial cells, is crucial for the separation and arrangement of angioblasts followed by endothelial cell assembly into cord-like vessels. 65 Concomitant and subsequent to endothelial cell convergence is the networking of blood vessels. Molecules such as neuropilins and plexins, the 2 classes of semaphorin receptors, are known to direct microvessel branching and/or guidance to their target sites. 40,66 An obvious conclusion from this cornucopia of studies is that blood vessel formation requires multiple pathways that talk among one another to coordinate the spatial and temporal differential gene expression pattern during blood vessel formation.

Vessel Fate

Interestingly, the fate of arterial, venous and lymphatic vessels are in part genetically determined early during vascular development before circulation and during the amalgamation of blood islands in the yolk sac. Molecules such as ephrins, ephrin receptors, neuropilin receptors, and type-A plexins serve as markers for arterial and venous identity, and appear well before the structuring of tube-like vessels. 67 Arterial cell fate appears to be determined by intersecting signaling cascades involving first sonic hedgehog (Shh), then VEGF, followed by the Notch pathway. 68 Loss of Shh or VEGF results in loss of arterial markers, whereas VEGF can rescue arterial differentiation in the absence of Shh signaling. The Notch pathway has also been reported to repress venous markers during the expression of artery-specific genes. 69 Ephrins and their tyrosine kinase receptors (Ephs) are required for arterio-venous communications. 70 Ephrin-B2, a membrane bound ligand with specificity toward the Eph-B4 receptor, marks arterial but not venous endothelial cells from the onset of vessel remodeling. However, Eph-B4 marks veins but not arteries. 71 The null phenotype for each of these genes is similar, suggesting reciprocal coordination between these molecules in the formation of capillary beds. 71 Finally, we have some knowledge of the molecular regulation controlling the formation of the lymphatic vasculature. The homeobox gene, Prox1, serves as a cue for the venous-derived lymphatic system, which is completely absent in mice null for this gene. 72 A Prox1-positive subpopulation of cardinal vein endothelial cells are transformed into lymphatic vessels via a VEGF-C–dependent mechanism. 73 Also, the developing lymphatic vasculature is disrupted by targeted inactivation of angiopoietin-2 in mice. 74 Although several markers and stimuli of vessel morphogenesis are identified, much remains to be elucidated in the molecular regulation of these processes, particularly the responsible signaling pathways.

Models of Vasculogenesis

Although the vascular system remains a comparatively difficult “organ” to study developmentally because of its dispersed architecture and diverse cellular origins, model organisms, and culture systems characterized and developed mostly over the past 15 years have greatly accelerated our understanding of the molecular mechanisms of vascular development. Vascular biologists now have many tools at their disposal—including, but not limited to, those described here.

Whole Animal Models

There is no question that whole organisms provide the most physiologically relevant systems in which to study vascular development. Vascular biologists have used a number of model organisms, each with distinct advantages, to discover the mechanisms of vasculogenesis. Avian embryos were used from the very beginning of vascular developmental biology and continue to be used today because of their experimental accessibility and amenability to elegant chimeric analyses, in combination with vascular and species-specific reagents such as the QH1 antibody. 75 These experimental approaches have been further complemented by recent advances in viral cell labeling, which has greatly facilitated vascular cell lineage analysis, especially in the coronary vasculature. 24 Xenopus laevis embryos are ideal for studies involving early cell fate determination and inductive signals caused by their temporally controlled development and anatomically defined germ layers. 5 However, the genetic workhorses of vascular development have been the zebrafish and mouse. The rapid development and visibility of the zebrafish vasculature have facilitated high-throughput chemical mutant phenotype screens that have uncovered roles for previously unsuspected genes in cardiovascular development. 76,77 Finally, mouse studies have been invaluable to the identification of key components in the molecular regulation of endothelial differentiation. Because of the early dependence of the developing embryo on the establishment of a functional blood supply, genetic mutations that affect early blood vessel cell differentiation often result in embryonically lethal phenotypes (Table). Continued progress in the development of conditional knockout technologies combined with the further characterization of early vascular lineage-specific promoters will provide invaluable tools for investigations into specific gene function and expression, as well as vascular cell lineage analysis. 78,79

Explant Culture Models

Whereas whole-animal models offer great physiological relevance, they are difficult to manipulate experimentally. To circumvent this difficulty, researchers have recently developed ex vivo models of tissue culture in which portions of vasculogenic tissue can be excised and manipulated in defined culture conditions. Two such models include culture of the murine allantois 80 and the avian PE. 25 Although the culture time of the murine allantois is short (&2 days), the vasculogenic changes during this time are rapid (including the de novo formation of a vascular plexus) and, importantly, can be manipulated pharmacologically. However, the avian PE can be propagated in culture for up to 2 weeks, allowing for more elaborate biological manipulation. During this time important cellular changes that occur in the PE in vivo, including EMT and progenitor cell differentiation, are recapitulated in vitro and can be monitored over time. 23 Further characterization of both of these models will be useful for the elucidation of molecular mechanisms underlying, but perhaps not limited to, allantoic and coronary vasculogenesis.

Embryonic Stem Cells

Embryonic stem (ES) cells, especially those of murine origin, have revolutionized our ability to investigate the process of blood vessel development. They have been used to study not only the earliest stages of endothelial specification, 7,8,46 but also later morphogenetic processes in the primitive vasculature. 56 In fact, vascular differentiation in the embryoid body (EB) system so closely recapitulates that of early in vivo vascular development that it has been suggested that phenotypes of genetic mutant animals can be predicted from the phenotypes of their cognate ES cells in culture. 81–83 Furthermore, the accessibility of this system has allowed genome-wide gene-trap analyses to identify novel genes whose expression is confined to the developing vasculature. 84

In addition to the EB model of ES cell differentiation, ES cells cultured under tightly defined conditions to promote the growth of specific lineages have been used to support and study the role of lineage-specific precursors, especially hemangioblasts, during development. 7 In fact, these same culture conditions have recently been used to determine that cells with potential to differentiate into both blood and endothelial cells exist in the posterior primitive streak of the early murine embryo. 15 It is clear that the culture conditions (media, coated dishes, feeder cells, cystic embryoid body formation, etc) play important roles not only in the kinetics but also in the extent of endothelial differentiation in these systems. It is also important to note that these stem cell systems are devoid of blood flow and lack the spatial organization of the developing embryo, perhaps limiting their usefulness as physiologically relevant models of later vascular biologic processes.

Conclusions

The experimental database that we use to understand endothelial differentiation and vascular development is exceptionally rich and draws on approaches that range from the imaginatively observational to the rigorously inductive. A number of key controversies in developmental biology have concerned the origin of endothelial cells and the means by which blood vessels are assembled. It has become obvious during the past decade that many of the principles of blood vessel development also apply to the assembly and disassembly of blood vessels in the adult, particularly in pathological circumstances. Activators and inhibitors of developmental pathways have been tested for their ability to modulate angiogenesis in early phase clinical trials, and in the case of anti-Flk1 antibodies clinical utility has been demonstrated for anti-tumor strategies.

Likewise, the explosion of interest in stem cell biology and the potential for regenerative medicine have caused many to reconsider the usefulness of understanding vascular developmental events with the notion that many of the pathways identified may be recapitulated in adult stem cells as they are coaxed toward the vascular lineage. Analyses of circulating endothelial progenitor cells, which have angiogenic potential, do indeed suggest that there are similarities in the biology of these cells compared with developmental endothelial precursors. Stem cell therapeutics therefore represents another potential arena for translation of insights from vascular development to clinical practice.

Even though our understanding of endothelial development is much richer than it was even a few years ago and despite the potential applications of this knowledge in clinical medicine, there are still a number of key issues on this topic that remain to be resolved. Precisely how early are endothelial precursors specified during development, and what is the nature of this progenitor cell pool? What are the relationships among signaling pathways that specify endothelial fates in a coordinated fashion? Is there a transcriptional hierarchy that regulates vascular development? The answers to these and other questions about endothelial development are likely to be forthcoming in the near future as experimental methods continue to evolve.


White Blood Cells

White blood cells are a family of many different cell types that mediate many different functions including: immune defence, clotting, bacteria and virus destruction and cell debris scavenging. These cells are not formed in the initial embryonic blood, mainly nucleated erythroid cells RBCs with small numbers of macrophages and megakaryocytes. White blood cells begin to develop in the early fetal period. ⎛] The fetal and neonatal neutraphils differ from adult neutrophils, based upon their maturation and environmental factors. These cells will form the majority of granulocyte precursors within the bone marrow.


Second trimester (GA 15-21) fetal blood study ⎜] showed significant changes in erythropoietic system though little change in myeloid series, with no significant increase or decrease in numbers. The only exception was eosinophils and basophils which increase significantly with gestational age while the platelet count remains constant.

Third trimester fetal cord blood study ⎝] showed no gender differences in counts of white blood cells, neutrophils, monocytes, eosinophils and lymphocytes that all increased. Platelets also increased from 30-35 weeks. The percentages of lymphocytes and monocytes decreased overall though, due to the large increase in the absolute neutrophil count.

Tissue Macrophages

Adult - liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) lung (alveolar macrophages)

Arise from erythro-myeloid progenitors (EMPs) in the yolk sac that are a separate population from haematopoietic stem cells (HSCs) ⎞]


Primary Vesicles

As the anterior end of the neural tube starts to develop into the brain, it undergoes a couple of enlargements the result is the production of sac-like vesicles. Similar to a child’s balloon animal, the long, straight neural tube begins to take on a new shape. Three vesicles form at the first stage, which are called primary vesicles. These vesicles are given names that are based on Greek words, the main root word being enkephalon, which means “brain” (en- = “inside” kephalon = “head”). The prefix to each generally corresponds to its position along the length of the developing nervous system.

The prosencephalonforebrain. The mesencephalon (mes- = “middle”) is the next vesicle, which can be called the midbrain. The third vesicle at this stage is the rhombencephalon. The first part of this word is also the root of the word rhombus, which is a geometrical figure with four sides of equal length (a square is a rhombus with 90° angles). Whereas prosencephalon and mesencephalon translate into the English words forebrain and midbrain, there is not a word for “four-sided-figure-brain.” However, the third vesicle can be called the hindbrain. One way of thinking about how the brain is arranged is to use these three regions—forebrain, midbrain, and hindbrain—which are based on the primary vesicle stage of development (Figure 14.1.2a).


6.7: Development of Blood Vessels and Fetal Circulation - Biology

The peripheral vascular system (PVS) includes all the blood vessels that exist outside the heart. The peripheral vascular system is classified as follows: The aorta and its branches:

  • The arterioles
  • The capillaries
  • The venules and veins returning blood to the heart

The function and structure of each segment of the peripheral vascular system vary depending on the organ it supplies. Aside from capillaries, blood vessels are all made of three layers: 

  • The adventitia or outer layer which provides structural support and shape to the vessel
  • The tunica media or a middle layer composed of elastic and muscular tissue which regulates the internal diameter of the vessel
  • The tunic intima or an inner layer consisting of an endothelial lining which provides a frictionless pathway for the movement of blood

Within each layer, the amount of muscle and collagen fibrils varies, depending on the size and location of the vessel. 

Arteries play a major role in nourishing organs with blood and nutrients. Arteries are always under high pressure. To accommodate this stress, they have an abundance of elastic tissue and less smooth muscle. The presence of elastin in the large blood vessels enables these vessels to increase in size and alter their diameter. When an artery reaches a particular organ, it undergoes a further division into smaller vessels that have more smooth muscle and less elastic tissue. As the diameter of the blood vessels decreases, the velocity of blood flow also diminishes. Estimates are that about 10% to 15% of the total blood volume is contained in the arterial system. This feature of high systemic pressure and low volume is typical of the arterial system.  

 There are two main types of arteries found in the body: (1) the elastic arteries, and (2) the muscular arteries. Muscular arteries include the anatomically named arteries like the brachial artery, the radial artery, and the femoral artery, for example. Muscular arteries contain more smooth muscle cells in the tunica media layer than the elastic arteries. Elastic arteries are those nearest the heart (aorta and pulmonary arteries) that contain much more elastic tissue in the tunica media than muscular arteries. This feature of the elastic arteries allows them to maintain a relatively constant pressure gradient despite the constant pumping action of the heart.  

Arterioles provide blood to the organs and are chiefly composed of smooth muscle. The autonomic nervous system influences the diameter and shape of arterioles. They respond to the tissue's need for more nutrients/oxygen. Arterioles play a significant role in the systemic vascular resistance because of the lack of significant elastic tissue in the walls. 

The arterioles vary fromو to 60 micrometers. The arterioles further subdivide into meta-arterioles. 

Capillaries 

Capillaries are thin-walled vessels composed of a single endothelial layer. Because of the thin walls of the capillary, the exchange of nutrients and metabolites occurs primarily via diffusion. The arteriolar lumen regulates the flow of blood through the capillaries. 

Venules are the smallest veins and receive blood from capillaries. They also play a role in the exchange of oxygen and nutrients for water products. There are post-capillary sphincters located between the capillaries and venules. The venule is very thin-walled and easily prone to rupture with excessive volume. 

Blood flows from venules into larger veins. Just like the arterial system, three layers make up the vein walls. But unlike the arteries, the venous pressure is low. Veins are thin-walled and are less elastic. This feature permits the veins to hold a very high percentage of the blood in circulation. The venous system can accommodate a large volume of blood at relatively low pressures, a feature termed high capacitance. At any point in time, nearly three-fourths of the circulating blood volume is contained in the venous system. One can also find one-way valves inside veins that allow for blood flow, toward the heart, in a forward direction. Muscle contractions aid the blood flow in the leg veins. The forward blood flow from the lower extremities to the heart is also influenced by respiratory changes that affect pressure gradients in the abdomen and chest cavity. This pressure differential is highest during deep inspiration, but a small pressure differential is observable during the entire respiratory cycle. 

Structure and Function

Vessels transport nutrients to organs/tissues and to transport wastes away from organs/tissues in the blood. A primary purpose and significant role of the vasculature is its participation in oxygenating the body.[1] Deoxygenated blood from the peripheral veins is transported back to the heart from capillaries, to venules, to veins, to the right side of the heart, and then to the lungs. Oxygenated blood from the lungs is transported to the left side of the heart into the aorta, then to arteries, arterioles, and finally capillaries where the exchange of nutrients occurs. Loading and unloading of oxygen and nutrients occur mostly in the capillaries.   

Embryology

Blood vessels arise from the mesodermal embryonic layer. Embryonic development of vessels and the heart begins in the middle of the third week of life. Fetal circulation through this vasculature system begins around the eighth week of development. 

Blood vessel formation occurs via two main mechanisms: (1) vasculogenesis and (2) angiogenesis.

Vasculogenesis is the process by which blood vessels form in the embryo. Interactions between precursor cells and various growth factors drive the cellular differentiation seen with vasculogenesis[2]. Precursor mesodermal cells and their receptors respond to FGF2 to become hemangioblasts. Hemangioblast receptors then respond to VEGF, inducing further differentiation into endothelial cells.[3] These endothelial cells then coalesce, forming the first hollow blood vessels. The first blood vessels formed by vasculogenesis include the dorsal aorta and the cardinal veins.

All other vasculature in the human body forms by angiogenesis. Angiogenesis is the process in which new blood vessels derive from the endothelial layer of a pre-existing vessel. Interactions involving VEGF drive angiogenesis. This process is the predominant form of neovascularization in the adult.  

Blood Supply and Lymphatics

The walls of large blood vessels, like the aorta and the vena cava, are supplied with blood by vasa vasorum. This term translates to mean "vessel of a vessel." 

 Three types of vasa vasorum exist (1) vasa vasorum internae, (2) vasa vasorum externae, and (3) venous vasa vasorae. Vasa vasorum internae originate from the lumen of a vessel and penetrate the vessel wall to supply oxygen and nutrients. Vasa vasorum externae originate from a nearby branching vessel and feedback into the larger vessel wall[4]. Some infections, such as late-stage manifestations of tertiary syphilis may lead to endarteritis of the vasa vasorum of the ascending aorta.[5] Venous vasa vasorae originate within the vessel wall and drain into a nearby vein to provide venous drainage for vessel walls. 

Nerves

The sympathetic nervous system primarily innervates blood vessels. The smooth muscles of vasculature contain alpha-1, alpha-2, and beta-2 receptors.[6] A delicate balance between the influence of the sympathetic and parasympathetic nervous systems is responsible for the underlying physiological vascular tone. Specialized receptors located in the aortic arch and the carotid arteries acquire information regarding blood pressure (baroreceptors) and oxygen content (chemoreceptors) from passing blood. This information is then relayed to the nucleus of the solitary tract via the vagus nerve.[7] Blood vessel constriction or relaxation then ensues accordingly, determined by the body's sympathetic response.  

Muscles

Blood vessels contain only smooth muscle cells. These muscle cells reside within the tunica media along with elastic fibers and connective tissue. Although vessels only contain smooth muscles, the contraction of skeletal muscle plays an important role in the movement of blood from the periphery towards the heart in the venous system. 

Surgical Considerations

Injury to many blood vessels could have potentially serious implications. A rule of successful surgery is that a surgical site must have both adequate arterial supply and adequate venous drainage. Lack of either will result in suboptimal outcomes and complications for the patient. Special consideration must be given to avoid injury to the larger vessels (IVC, aorta, etc.) and any vessel particularly susceptible during specific surgical procedures.[8]

Clinical Significance

Damage or disease of the blood vessels causes a variety of diseases including hypertension, aneurysm formation, aneurysm rupture, peripheral vascular disease, deep venous thrombosis, pulmonary embolism, transient ischemic attack, stroke, and many others. Some diseases are directly related to inherent vessel disease, while others are side effects of vessel disease.[9][10] Clinically, vascular disease is an important problem. The CDC attributes $1 billion per day in cost to cardiovascular disease and stroke in the United States.


References

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Reviews

Sutherland AE. (2016). Tissue morphodynamics shaping the early mouse embryo. Semin. Cell Dev. Biol. , 55, 89-98. PMID: 26820524 DOI.

Rossant J. (2016). Making the Mouse Blastocyst: Past, Present, and Future. Curr. Top. Dev. Biol. , 117, 275-88. PMID: 26969983 DOI.

Swartley OM, Foley JF, Livingston DP, Cullen JM & Elmore SA. (2016). Histology Atlas of the Developing Mouse Hepatobiliary Hemolymphatic Vascular System with Emphasis on Embryonic Days 11.5-18.5 and Early Postnatal Development. Toxicol Pathol , 44, 705-25. PMID: 26961180 DOI.

Savolainen SM, Foley JF & Elmore SA. (2009). Histology atlas of the developing mouse heart with emphasis on E11.5 to E18.5. Toxicol Pathol , 37, 395-414. PMID: 19359541 DOI.


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