Cardiovascular System

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Chapter 17

Cardiovascular System

This chapter follows the development of the heart from a simple tubular structure to the four-chambered organ that can assume the full burden of maintaining an independent circulation at birth. Similarly, the pattern of blood vessels is traced from their first appearance to an integrated system that carries blood to all parts of the embryo and the placenta. (The early stages in the establishment of the heart and blood vessels are described in Chapter 6 [see Figs. 6.14 to 6.19], and the general plan of the embryonic circulation is summarized in Figure 6.26.) Cellular aspects of blood formation are also briefly described. Clinical Correlations 17.1 and 17.2 at the end of the chapter discuss malformations of the heart and the blood vessels. Table 17.6, also at the end of the chapter, summarizes the timelines in cardiac development.

Functionally, the embryonic heart needs only to act like a simple pump that maintains the flow of blood through the body of the embryo and into the placenta, where fetal wastes are exchanged for oxygen and nutrients. An equally important function, however, is to anticipate the radical changes in the circulation that occur at birth as a consequence of the abrupt cutting off of the placental circulation and the initiation of breathing. To meet the complex requirements of the postnatal circulatory system, the embryonic heart must develop four chambers that can receive or pump the full flow of blood circulating throughout the body. The heart must also adapt to the condition of the fetal lungs, which are poorly developed and for much of the fetal period do not possess a vasculature that can accommodate a large flow of blood. This physiological dilemma is resolved by the presence of two shunts that allow each chamber of the heart to handle large amounts of blood while sparing the underdeveloped pulmonary vascular channels.

Cardiac morphogenesis involves intrinsic cellular and molecular interactions, but these must occur against a background of ongoing mechanical function. Some of these mechanisms remain elusive, but others are becoming better defined through research on normal and abnormal cardiac development.

Development of the vasculature at the level of gross patterns of arteries and veins has been well understood for many years. More recently, new cellular and molecular markers have enabled investigators to outline the cellular origins and factors controlling differentiation of the arteries and veins in specific organs or regions of the body.

Development of Blood and the Vascular System

Development of the vascular system begins in the wall of the yolk sac during the third week of gestation (18 days) with the formation of blood islands (see Fig. 6.19). At this time, the embryo has attained a size that is too large for the distribution of oxygen to all tissues by diffusion alone. This situation necessitates the very early development of the heart and the vascular system. Because the tissues that normally produce blood cells in an adult have not yet begun to form, yolk sac hematopoiesis serves as a temporary adaptation for accommodating the immediate needs of the embryo.

The origin and nature of the cells constituting the blood islands are the subjects of two major hypotheses. According to a long-standing hypothesis, founder cells of the blood islands, called hemangioblasts, have a bipotential developmental capacity and can give rise to either endothelial cells or hematopoietic stem cells. When a commitment has been made to one of these two lineages, daughter cells lose the capacity to form the other type of cell. A more recent hypothesis posits that by the time the yolk sac is colonized by hemangioblasts, these cells have already been segregated into hematopoietic and endothelial lineages. Research on mouse embryos suggests that instead of blood islands, the hematopoietic cells aggregate into a blood band that surrounds the yolk sac.

Embryonic Hematopoiesis

Hemangiogenic precursor cells first arise in the posterolateral mesoderm during gastrulation and from there migrate to the earliest blood-forming organs (Fig. 17.1). Under the influence of Runx-1, some of their progeny follow the hematopoietic lineage, whereas others, responding to Hoxa3, enter the endothelial lineage. Still other progeny will enter a third lineage and eventually form vascular smooth muscle cells. Although blood cell formation (hematopoiesis) begins in the yolk sac, the yolk sac–derived cells are soon replaced by blood cells that are independently derived from other sites of hematopoiesis (Fig. 17.2).

The blood islands contain pluripotential hematopoietic stem cells, which can give rise to most types of cells found in the embryonic blood. The erythrocytes produced in the yolk sac are large nucleated cells that enter the bloodstream just before the heart tube begins to beat at about 22 days’ gestation. For the first 6 weeks, the circulating erythrocytes are largely yolk sac derived, but during that time, preparations for the next stages of hematopoiesis are taking place.

Analysis of human embryos has shown that, starting at 28 days, definitive intraembryonic hematopoiesis begins in small clusters of cells (para-aortic clusters) in the splanchnopleuric mesoderm associated with the ventral wall of the dorsal aorta and shortly thereafter in the aorta/genital ridge/mesonephros (AGM) region. Precursor cells from the AGM region make their way via the blood to blood-forming sites in the liver, the yolk sac, and the placenta. Hematopoietic stem cells formed in the AGM, the yolk sac, and the placenta become transported to the liver via the circulation to the liver (see Fig. 17.1). By 5 to 6 weeks of gestation, sites of hematopoiesis become prominent in the liver. In both the yolk sac and the early sites of embryonic hematopoiesis, the endothelial cells themselves briefly retain the capacity for producing blood-forming cells. There is now evidence that in the AGM region, nitric oxide gas signaling, resulting from shear stress caused by blood flow on the endothelial cells, can induce their transformation into hematopoietic stem cells.

The erythrocytes produced by the liver are quite different from the erythrocytes derived from the yolk sac. Although still considerably larger than normal adult red blood cells, liver-derived erythrocytes are non-nucleated and contain different types of hemoglobin. By 6 to 8 weeks of gestation in humans, the liver replaces the yolk sac as the main source of blood cells. Although the liver continues to produce red blood cells until the early neonatal period, its contribution begins to decline in the sixth month of pregnancy. At this time, the formation of blood cells shifts to the bone marrow, the definitive site of adult hematopoiesis. This shift is controlled by cortisol secreted by the fetal adrenal cortex. In the absence of cortisol, hematopoiesis remains confined to the liver. Before hematopoiesis becomes well established in the bone marrow, small amounts of blood formation may also occur in the omentum and possibly the spleen.

Cellular Aspects of Hematopoiesis

The first hematopoietic stem cells that arise in the embryo are truly pluripotential in that they can give rise to all the cell types found in the blood (Fig. 17.3). These pluripotent stem cells, sometimes called hemocytoblasts, have great proliferative ability. They produce vast numbers of progeny, most of which are cells at the next stage of differentiation, but they also produce small numbers of their original stem cell type, which act as a reserve capable of replenishing individual lines of cells should the need arise. Very early in development, the line of active blood-forming cells subdivides into two separate lineages. Lymphoid stem cells ultimately form the two lines of lymphocytes: B lymphocytes (which are responsible for antibody production) and T lymphocytes (which are responsible for cellular immune reactions). Myeloid stem cells are precursors to the other lines of blood cells: erythrocytes, the granulocytes (neutrophils, eosinophils, and basophils), monocytes, and platelets. The second-generation stem cells (lymphoid and myeloid) are still pluripotent, although their developmental potency is restricted because neither lymphoid cells nor myeloid cells can form the progeny of the other type.

Stemming from their behavior in certain experimental situations, the hematopoietic stem cells are often called colony-forming units (CFUs). The first-generation stem cell is called the CFU-ML because it can give rise to myeloid and lymphoid lines of cells. Stem cells of the second generation are called CFU-L (lymphocytes) and CFU-S (spleen) (determined from experiments in which stem cell differentiation was studied in irradiated spleens). In some cases, the progeny of CFU-ML and CFU-S are committed stem cells, which are capable of forming only one type of mature blood cell. For each lineage, the forming cell types must pass through several stages of differentiation before they attain their mature phenotype.

What controls the diversification of stem cells into specific cell lines? Experiments begun in the 1970s provided evidence for the existence of specific colony-stimulating factors (CSFs) for each line of blood cell. CSFs are diffusible proteins that stimulate the proliferation of hematopoietic stem cells. Some CSFs act on several types of stem cells; others stimulate only one type. Although much remains to be learned about the sites of origin and modes of action of CSFs, many CSFs seem to be produced locally in stromal cells of the bone marrow, and some may be stored on the local extracellular matrix. CSFs are bound by small numbers of surface receptors on their target stem cells. Functionally, CSFs represent mechanisms for stimulating the expansion of specific types of blood cells when the need arises. Recognition of the existence of CSFs has prompted considerable interest in their clinical application to conditions characterized by a deficiency of white blood cells (leukopenia).

Certain Hox genes, especially those of the Hoxa and Hoxb families, play an important role in some aspects of hematopoiesis. Exposure of bone marrow to antisense oligonucleotides against specific Hox genes results in the suppression of specific lines of differentiation of blood cells. Conversely, engineered overexpression of genes, such as Hoxb8, Hoxa9, and Hoxa10, causes leukemia in mice. Evidence is increasing for the involvement of Hox genes in the pathogenesis of human leukemias. One important function of the Hox genes in hematopoiesis is the regulation of proliferation. Several growth factors, especially bone morphogenetic protein-4 (BMP-4), Indian hedgehog, and Wnt proteins, are important in stimulating and maintaining hematopoietic stem cell activity.


Red blood cell formation (erythropoiesis) occurs in three waves during the embryonic period. The first wave begins with precursors within the yolk sac, which produce primitive nucleated erythrocytes that mature within the bloodstream. The second wave also begins in the yolk sac, but the precursor cells then colonize the embryonic liver and produce the first of a generation of definitive fetal erythrocytes that are dominant during the prenatal period. The third wave consists of precursor cells that enter the liver from the AGM mesoderm and the placenta. Some of these definitive erythroid progenitor cells send progeny directly from the liver into the bloodstream as definitive fetal erythrocytes. Others seed the bone marrow and produce adult-type erythrocytes later in the fetal period.

The erythrocyte lineage represents one line of descent from the CFU-S cells. Although the erythroid progenitor cells are restricted to forming only red blood cells, there are many generations of precursor cells (Fig. 17.4). The earliest stages of erythropoiesis are recognized by the behavior of the precursor cells in culture, rather than by morphological or biochemical differences. These are called erythroid burst-forming units (BFU-E) and erythroid CFUs (CFU-E). Each responds to different stimulatory factors. The pluripotent CFU-S precursors (see Fig. 17.3) respond to interleukin-3, a product of macrophages in adult bone marrow. A hormone designated as burst-promoting activity stimulates mitosis of the BFU-E precursors (see Fig. 17.4). A CFU-E cell, which has a lesser proliferative capacity than a BFU-E cell, requires the presence of erythropoietin as a stimulatory factor.

Erythropoietin is a glycoprotein that stimulates the synthesis of the mRNA for globin and is first produced in the fetal liver. Later in development, synthesis shifts to the kidney, which remains the site of erythropoietin production in adults. Under conditions of hypoxia (e.g., from blood loss or high altitudes), the production of erythropoietin by the kidneys increases, thereby stimulating the production of more red blood cells to compensate for the increased need. In adult erythropoiesis, the CFU-E stage seems to be the one most responsive to environmental influences. The placenta is apparently impervious to erythropoietin, and this property insulates the embryo from changes in erythropoietin levels of the mother and eliminates the influence of fetal erythropoietin on the blood-forming apparatus of the mother.

One or two generations after the CFU-E stage, successive generations of erythrocyte precursor cells can be recognized by their morphology. The first recognizable stage is the proerythroblast (Fig. 17.5), a large, highly basophilic cell that has not yet produced sufficient hemoglobin to be detected by cytochemical analysis. Such a cell has a large nucleolus, much uncondensed nuclear chromatin, numerous ribosomes, and a high concentration of globin mRNAs. These are classic cytological characteristics of an undifferentiated cell.

Succeeding stages of erythroid differentiation (basophilic, polychromatophilic, and orthochromatic erythroblasts) are characterized by a progressive change in the balance between the accumulation of newly synthesized hemoglobin and the decline of first the RNA-producing machinery and later the protein-synthesizing apparatus. The overall size of the cell decreases, and the nucleus becomes increasingly pyknotic (smaller with more condensed chromatin) until it is finally extruded at the stage of the orthochromatic erythrocyte. After the loss of the nucleus and most cytoplasmic organelles, the immature red blood cell, which still contains a small number of polysomes, is a reticulocyte. Reticulocytes are released into the bloodstream, where they continue to produce small amounts of hemoglobin for 1 or 2 days.

The final stage of hematopoiesis is the mature erythrocyte, which is a terminally differentiated cell because of the loss of its nucleus and most of its cytoplasmic organelles. Erythrocytes in embryos are larger than their adult counterparts and have a shorter life span (50 to 70 days in the fetus versus 120 days in adults).

Hemoglobin Synthesis and its Control

Both the red blood cells and the hemoglobin within them undergo isoform transitions during embryonic development. The adult hemoglobin molecule is a complex composed of heme and four globin chains: two α and two β chains. The α and β subunits are products of genes located on chromosomes 16 and 11 (Fig. 17.6). Different isoforms of the subunits are encoded linearly on these chromosomes.

During the period of yolk sac hematopoiesis, embryonic globin isoforms are produced. The earliest embryonic hemoglobin, sometimes called Gower 1, is composed of two ζ (α-type) and two ε (β-type) chains. After passing through a couple of transitional forms (Table 17.1), hemoglobin synthesis enters a fetal stage by 12 weeks, which corresponds to the shift in the site of erythropoiesis from the yolk sac to the liver. Fetal hemoglobin consists of two adult-type α chains, which form very early in embryogenesis, and two γ chains, the major fetal isoform of the β chain. Fetal hemoglobin is the predominant form during the remainder of pregnancy. The main adaptive value of the fetal isoform of hemoglobin is that it has a higher affinity for oxygen than the adult form. This is advantageous to the fetus, which depends on the oxygen concentration of the maternal blood. Starting at about 30 weeks’ gestation, there is a gradual switch from the fetal to the adult type of hemoglobin, with α2β2 being the predominant type. A minor but functionally similar variant is α2δ2.

Table 17.1

Developmental Isoforms of Human Hemoglobin

Developmental Stage Hemoglobin Type Globin Chain Composition
Embryo Gower 1 ζ2ε2
Embryo Gower 2 α2ε2
Embryo Portland ζ2γ2
Embryo to fetus Fetal α2γ2
Fetus to adult A (adult) α2β2
Adult A2 α2δ2
Adult Fetal α2γ2*


*The fetal hemoglobin expressed in adults differs from true fetal hemoglobin by an amino acid substitution at the 136 position of the γ chain.

Adapted from Brown MS: In Stockman J, Pochedly C, eds: Developmental and neonatal hematology, New York, 1988, Raven Press.

Formation of Embryonic Blood Vessels

The early embryo is devoid of blood vessels. Although blood islands appear in the wall of the yolk sac, and extraembryonic vascular channels form in association with them (see Fig. 6.19), much of the vasculature of the embryonic body is derived from intraembryonic sources. During the early period of somite formation, networks of small vessels rapidly appear in many regions of the embryonic body.

The formation of blood vessels in the embryo consists of several phases (Fig. 17.7). The first is the specification of a population of vascular precursors, called angioblasts. These cells become organized into a primary capillary plexus through a process known as vasculogenesis. To keep pace with the rapidly growing embryo, the primary capillary plexus must rapidly undergo reorganization through the resorption of existing vessels and the sprouting of new branches to support the expanding vascular network. This latter process is called angiogenesis. Angiogenesis continues not only in the prenatal period, but also throughout adult life, as tissues and organs continually adapt to changing conditions of life, whether normal or pathological.

Detailed descriptive studies and transplantation experiments involving intrinsic cellular labels or graft-specific monoclonal antibody labels have shown that angioblasts arise from most mesodermal tissues of the body, except notochord and prechordal mesoderm (Table 17.2). Embryonic blood vessels form from angioblasts by three main mechanisms. Many of the larger blood vessels, such as the dorsal aortae, are formed by the coalescence of angioblasts in situ. Other equally large channels, such as the endocardium, are formed by angioblasts migrating into the region from other sites. Other vessels, especially the intersegmental vessels of the main body axis and vessels of the central nervous system, arise as vascular sprouts from existing larger vessels. Many of the angioblasts of the trunk are originally associated with the splanchnic mesoderm.

Table 17.2

Distribution of Endogenous Angioblasts in Embryonic Tissues

Tissues Angioblasts
Paraxial mesoderm +
Lateral mesoderm +
Prechordal mesoderm
Neural crest
Whole somites +
Dorsal half somites +
Segmental plate mesoderm +
Lateral somatic mesoderm +
Lateral splanchnic mesoderm +
Spinal cord


From Noden DM: Ann NY Acad Sci 588:236-249, 1990.

The developmental processes leading to the initial formation of the aorta are beginning to be understood. The endothelium of the early paired aortae is derived from splanchnopleure and requires an interaction with the underlying endoderm for its development. While the aortae are still in the paired stage, somite-derived cells contribute to their dorsal walls. Concomitantly, the ventral splanchnopleure-derived endothelium begins to give rise to clusters of hematopoietic stem cells. Then the dorsal somite-derived endothelial cells overgrow the ventral splanchnopleure-derived endothelial cells. When this is completed, hematopoiesis in the aorta ceases.

All stages in the formation of the vascular system occur in response to the influence of powerful growth factors and their receptors. The initial phase of recruitment of a population of angioblasts from the mesoderm is characterized by the appearance of a transmembrane vascular endothelial growth factor receptor (VEGFR-2) on their surfaces (see Fig. 17.7). Soon, in response to the production of vascular endothelial growth factor (VEGF-A) by the surrounding mesenchyme, the phase of vasculogenesis occurs, and the angioblasts form the cellular tubes that become the basis for the primary capillary plexus.

The formation of vascular endothelial sprouts, the cellular basis for angiogenesis, occurs against a background of VEGF/VEGFR-1 and VEGF/VEGFR-2 interactions, but with a new set of players added. A sprouting factor, angiopoietin-1, interacts with its receptor, Tie-2, on the endothelial cells at sites where endothelial sprouts will occur. The Notch signaling pathway is also strongly tied to the formation of vascular sprouts (a common denominator with other organ systems that display branching morphogenesis), but its connection to the angiopoietin-1/Tie-2 mechanism remains unclear.

The next step in building a blood vessel is formation of the vascular wall, which in the trunk and extremities is derived from local mesoderm that becomes associated with the endothelial lining of the vessel. In the head and many areas of the aortic arch system, mesenchyme derived from neural crest ectoderm is a major contributor to the connective tissue and smooth muscle of the vascular wall. The neural crest, however, does not give rise to endothelial cells.

Two-way molecular signaling is involved in building up the walls of blood vessels. In response to the angiopoietin-1/Tie-2 interaction that occurs during angiogenesis, the endothelial cells release their own signaling molecule, platelet-derived growth factor, which stimulates the migration of mesenchymal cells toward the vascular endothelium. The release of other growth factors (transforming growth factor-β [TGF-β] and myocardin, a master regulator of smooth muscle formation) by the endothelial cells stimulates the differentiation of the mesenchymal cells into vascular smooth muscle or pericytes.

Research has shed considerable light on the differentiation of the arterial versus venous system. The arterial or venous identity of endothelial cells is established very early in their development, before angiogenesis and before the onset of circulation. The endothelial cells of developing arteries express the membrane-bound ligand Ephrin-B2, whereas the endothelial cells of developing veins express the receptor Eph-B4 on their surface membranes. These characteristic phenotypes are the results of different signaling cascades. Arterial vessels are the first to differentiate from generic endothelial background, and a set of signals, starting with sonic hedgehog (shh), finally leads to the acquisition of an arterial phenotype (Fig. 17.8). Notch, one of the links in that cascade, not only causes progression of the sequence of arterial differentiation leading to Ephrin-B2 expression, but it inhibits the expression of Eph-4 and the pathway leading to the venous phenotype. In what was earlier assumed to be a purely default mode, venous differentiation occurs under the influence of COUP-TFII (Chicken ovalbumin upstream promoter-transcription factor II), which suppresses the arterial pathway by inhibiting Notch signaling, but is a determinant of venous differentiation by acting upstream of Eph-4. Under the influence of Sox-18 and Prox-1, lymphatic vessels form and branch off from the veins. Prox-1 is a master regulator of venous identity. Later, physiological and local factors play a role in the differentiation of blood vessels. When the flow of blood to the yolk sac is greatly reduced, vessels slated to become arteries develop venous characteristics; correspondingly, developing veins exposed to high blood pressure transform into arteries.

As with myoblasts, angioblasts seem to react to local environmental cues that determine the specific morphological pattern of a blood vessel. An unexpected finding is that the pattern of the peripheral innervation often determines the pattern of the smaller arteries. The growing tips of endothelial cell buds and axonal growth cones of outgrowing nerve fibers contain receptors that respond remarkably similarly to the major families of environmental ligands (Table 17.3). VEGF, secreted by the nerve fibers, acts as an effective patterning agent for the blood vessels. The smooth muscle cells of the developing arteries secrete a factor, artemin, that guides the extension of sympathetic nerve fibers along the vessel wall.

Table 17.3

Responsiveness of Axonal Growth Cones and Endothelial Cell Tips to Environmental Ligands

Ligand Growth Cones Endothelial Tips
Semaphorin +
Netrin + +
Slit + +
Semaphorin + +
Ephrin + +
Netrin + +
Slit + +


VEGF, vascular endothelial growth factor.

Tracing studies of transplanted angioblasts have shown that some can of these cells migrate long distances. Angioblasts that have migrated far from the place into which they were grafted become integrated into morphologically normal blood vessels in the areas where they settle.

Local factors also influence the initiation of vasculogenesis. In some organs (e.g., the liver) or parts of organs (e.g., the bronchi of the respiratory system), the blood vessels supplying the regions arise from local mesoderm, whereas other organs (e.g., the metanephric kidneys) or parts of organs (e.g., the alveoli of the lungs) are supplied by blood vessels that grow into the mesenchyme from other tissues. In the latter type of vascularization mechanism, evidence is increasing that these organ primordia produce their own angiogenesis factors that stimulate the growth of vascular sprouts (by promoting mitosis of endothelial cells) into the glandular mesenchyme. Nearby blood vessels, in turn, influence the morphogenesis and differentiation of many structures (e.g., pancreas, glomerulus, liver) with which they are associated.

Development of the Arteries

Aorta, Aortic Arches, and Their Derivatives

The dorsal aorta forms from the direct aggregation of endothelial precursor cells derived from the lateral plate mesoderm. These cells form a vessel directly by a vasculogenesis mechanism. Vasculogenesis is stimulated by VEGF and other factors produced by the endoderm and BMP in the lateral mesoderm. When first formed, the cranial part of the dorsal aorta is a paired, with each member located lateral to the midline. The reason is that in the midline the notochord secretes the BMP antagonists noggin and chordin, which inhibit the activity of BMP and also inactivate the vasculogenic influences from the endoderm. Late in the fourth week, hematopoietic stem cells form in the lining of the ventral part of the aorta (see p. 409).

The system of aortic arches in early human embryos is organized along the same principles as the system of arteries supplying blood to the gills of many aquatic lower vertebrates. Blood exits from a common ventricle in the heart into a ventral aortic root, from which it is distributed through the branchial arches by pairs of aortic arches (Fig. 17.9A). In gilled vertebrates, the aortic arch arteries branch into capillary beds, where the blood becomes reoxygenated as it passes through the gills. In mammalian embryos, the aortic arches remain continuous vessels because gas exchange occurs in the placenta and not in the pharyngeal arches. The aortic arches empty into paired dorsal aortae where the blood enters the regular systemic circulation. In human embryos, all aortic arches are never present at the same time. Their formation and remodeling show a pronounced craniocaudal gradient. Blood from the outflow tract of the heart (the truncoconal region) flows into an aortic sac, which differs from the truncoconal region in the construction of its wall. The aortic arches branch off from the aortic sac.

The developmental anatomy of the aortic arch system illustrates well the principle of morphological adaptation of the vascular bed during different stages of embryogenesis (Table 17.4). Continued development of the cranial and cervical regions causes components of the first three arches and associated aortic roots to be remodeled into the carotid artery system (see Fig. 17.9). With the remodeling of the heart tube and the internal division of the outflow tract into aortic and pulmonary components, the fourth arches undergo an asymmetrical adaptation to the early asymmetry of the heart. The left fourth aortic arch is retained as a major channel (arch of the aorta), which carries the entire output from the left ventricle of the heart. The right fourth arch is incorporated into the right subclavian artery.

Table 17.4

Adult Derivatives of the Aortic Arch System

  Right Side Left Side
Aortic Arches
1 Disappearance of most of structure Disappearance of most of structure
Part of maxillary artery Part of maxillary artery
2 Disappearance of most of structure Disappearance of most of structure
Hyoid and stapedial arteries Hyoid and stapedial arteries
3 Ventral part—common carotid artery Ventral part—common carotid artery
Dorsal part—internal carotid artery Dorsal part—internal carotid artery
4 Proximal part of right subclavian artery Part of arch of aorta
5 Rarely recognizable, even in early embryo Rarely recognizable, even in early embryo
6 (pulmonary) Part of right pulmonary artery Ductus arteriosus
Part of left pulmonary artery
Ventral Aortic Roots
Cranial to third arch External carotid artery External carotid artery
Between third and fourth arches Common carotid artery Common carotid artery
Between fourth and sixth arches Right brachiocephalic artery Ascending part of aorta
Dorsal Aortic Roots
Cranial to third arch Internal carotid artery Internal carotid artery
Between third and fourth arches Disappearance of structure Disappearance of structure
Between fourth and pulmonary arches Central part of right subclavian artery Descending aorta
Caudal to pulmonary arch Disappearance of structure Descending aorta


Embryology textbooks traditionally depict the aortic arch system as consisting of six pairs of vascular arches, but the fifth and sixth arches never appear as discrete vascular channels similar to the first through fourth arches. The fifth aortic arch, if it exists at all, is represented by no more than a few capillary loops. The sixth (pulmonary arch) arises as a capillary plexus associated with the early trachea and lung buds. The capillary plexus is supplied by ventral segmental arteries arising from the paired dorsal aortae in that region (Fig. 17.10). The equivalent of the sixth arch is represented by a discrete distal segment (ventral segmental artery) connected to the dorsal aorta and a plexuslike proximal segment that establishes a connection between the aortic sac at the base of the fourth arch and the distal segmental component. As the respiratory diverticulum and early lung buds elongate, parts of the pulmonary capillary network consolidate to form a pair of discrete pulmonary arteries that connect to the putative sixth arch. Although the term sixth aortic arch is frequently used in anatomical and clinical literature, pulmonary arch is a more appropriate term because it does not imply equivalence to the other aortic arches.

Similar to the fourth aortic arch, the pulmonary arch develops asymmetrically. On the left side, it becomes a large channel. Its distal segment, which was derived from a ventral segmental artery, persists as a major channel (ductus arteriosus) that shunts blood from the left pulmonary artery to the aorta (see Fig. 17.9C). The lungs are protected by this shunt from a flow of blood that is greater than what their vasculature can handle during most of the intrauterine period. On the right side, the distal segment of the pulmonary arch regresses, and the proximal segment (the base of the right pulmonary artery) branches off from the pulmonary trunk.

The asymmetry of the derivatives of the pulmonary arch accounts for the difference between the course of the right and left recurrent laryngeal nerves, which are branches of the vagus nerve (cranial nerve X). These nerves, which supply the larynx, hook around the pulmonary arches. As the heart descends into the thoracic cavity from the cervical region, the branch point from the vagus of each recurrent laryngeal nerve is correspondingly moved. On the left side, the nerve is associated with the ductus arteriosus (see Fig. 17.9C), which persists throughout the fetal period, so it is pulled deep into the thoracic cavity. On the right side, with the regression of much of the right pulmonary arch, the nerve moves to the level of the fourth arch, which constitutes an anatomical barrier. The positions of the right and left recurrent laryngeal nerves in an adult reflect this asymmetry, with the right nerve curving under the right subclavian artery (fourth arch) and the left nerve hooking around the ligamentum arteriosum (the adult derivative of the ductus arteriosus, the distal segment of the left pulmonary arch).

As the aortic arches become modulated into their adult configuration, specialized baroreceptors begin to form. One of these is the carotid sinus, which is located in the proximal portion of each internal carotid artery and is innervated by fibers of the glossopharyngeal nerve. Similarly, baroreceptors located in the proximal part of the right subclavian artery and in the aortic arch between the left common carotid and subclavian arteries are innervated by branches of the vagus and recurrent laryngeal nerves. Chemosensory structures associated with the aortic arches are the paired carotid bodies, which are located at the bifurcation of the internal and external carotid arteries and are innervated by a sensory branch of the glossopharyngeal nerve and sympathetic nerve fibers from the superior cervical ganglion.

Major Branches of the Aorta

In the early embryo, when the dorsal aortae are still paired vessels, three sets of arterial branches arise from them—dorsal intersegmental, lateral segmental, and ventral segmental (Fig. 17.11). These branches undergo a variety of modifications in form before assuming their adult configurations (Table 17.5). The ventral segmental arteries arise as paired vessels that course over the dorsal and lateral walls of the gut and yolk sac. With the closure of the gut and the narrowing of the dorsal mesentery, certain branches fuse in the midline to form the celiac, superior, and inferior mesenteric arteries.

Table 17.5

Major Arterial Branches of the Aorta

Embryonic Vessels Adult Derivatives
Dorsal Intersegmental Branches (Paired)
Cervical intersegmental (1-16) Lateral branches joining to become vertebral arteries
Seventh intersegmentals Subclavian arteries
Thoracic intersegmentals Intercostal arteries
Lumbar intersegmentals Iliac arteries
Lateral Segmental Branches
Up to 20 pairs of vessels supplying the mesonephros Adrenal arteries, renal arteries, gonadal (ovarian or spermatic) arteries
Ventral Segmental Branches*
Vitelline vessels Celiac artery, superior and inferior mesenteric arteries
Allantoic vessels Umbilical arteries


*Originally paired in areas where the embryonic aorta itself consists of paired components.

The umbilical arteries begin as pure ventral segmental branches supplying allantoic mesoderm, but their bases later connect with lumbar intersegmental vessels. The most proximal umbilical channels then regress, and the intersegmental branches become their main branches off the aorta. Like their subclavian counterparts in the arms, the initially small arterial branches (iliac arteries) supplying the leg buds appear as components of the dorsal intersegmental (lumbar) branches of the aorta. After the umbilical arteries incorporate the proximal segments of the intersegmental vessels, the iliac arteries arise as branches off the umbilical arteries.

Arteries of the Head

The arteries supplying the head arise from two sources. Ventrally, the aortic arch system (first to third arches and corresponding roots) gives rise to the arteries supplying the face (external carotid arteries) and the frontal part of the base of the brain (internal carotid arteries) (see Fig. 17.9).

At the level of the spinal cord, the vertebral arteries, which form through connections of lateral branches of dorsal intersegmental arteries, grow toward the brain. Soon, they veer toward the midline and fuse with the basilar artery, which has already formed earlier from the fusion of the bilateral longitudinal neural arteries (Fig. 17.12). The longitudinal neural arteries, which run along the ventral sides of the brain from the midbrain through the caudal end of the hindbrain, represent the major arterial supply to the brain during the fourth week of development. The basilar artery runs along the ventral surface of the brainstem and supplies the brainstem with a series of paired arteries. As the basilar artery approaches the level of the diencephalon and the internal carotid arteries, sets of branches from each of these major vessels grow out and fuse, to form posterior communicating arteries, which join the circulations of the basilar and internal carotid arteries. Two other small branches off the internal carotid system fuse in the midline to complete a vascular ring (circle of Willis), which underlies the base of the diencephalon and encircles the optic chiasm and pituitary stalk. The circle of Willis is a structural adaptation that ensures a continuous blood supply in the event of occlusion of some major arteries supplying the brain. In addition, it is a structural landmark that marks the transition between mesodermally derived blood vessels of the trunk and those of the head, which are primarily of neural crest origin.

Coronary Arteries

Although intuitively one would expect the coronary arteries to arise as branches growing out from the aorta, experimental studies have shown instead that cellular precursors of the coronary arteries, arising in the same cellular primordium as the future epicardium, migrate toward the aorta and invade its wall (see Fig. 6.18B). The smooth muscle cells of the coronary vessels have a purely mesodermal origin, instead of the mixed neural crest and mesodermal origin seen in the aortic arch derivatives. Studies involving the tagging of cells with retroviral markers confirm that progenitor cells of the coronary vessels penetrate the wall of the already beating heart as the epicardial layer envelops the myocardium, and that after forming in situ, the coronary arteries secondarily enter the aorta.

Development of Veins

Veins follow a morphologically complex pattern of development characterized by the formation of highly irregular networks of capillaries and the ultimate expansion of certain channels into definitive veins. Because of the multichanneled beginnings and the number of options (Fig. 17.13), the adult venous system is characterized by a higher incidence of anatomical variations than the arterial system. A detailed description of the development of venous channels is beyond the scope of this text.

Cardinal Veins

The cardinal veins form the basis for the intraembryonic venous circulation. Several sets of cardinal veins appear at different times and in different locations. Within any set of cardinal veins, some segments regress, and others persist, either as independent channels or as components of composite veins that also include portions of other cardinal veins.

The earliest pattern of cardinal veins consists of paired anterior and posterior cardinal veins, which drain blood from the head and body into a pair of short common cardinal veins (see Fig. 17.13). The common cardinal veins, in turn, empty their blood into the sinus venosus of the primitive heart (see Fig. 17.15).

In the cranial region, the originally symmetrical anterior cardinal veins are transformed into the internal jugular veins