Embryology and Developmental Anatomy

Molecular Signaling of Vasculogenesis and Angiogenesis

Development of the vascular system is a complex orchestration of signaling molecules, receptor molecules, and transcription factors. This process starts with vasculogenesis , which begins with the modification of splanchnic mesodermal cells into angioblasts that form vesicular aggregates in the splanchnic mesoderm of the embryo and extraembryonic regions ( Fig. 2.1 ). ^, These angioblasts develop into flattened endothelial cells that form small vessel cords, which coalesce to form a primitive capillary plexus. This process is driven in large part by the signaling protein vascular endothelial growth factor (VEGF). The process of vasculogenesis is restricted to embryogenesis.

Once endothelial cells are established as vascular elements, they begin to sprout and bud, forming simple capillary networks in response to the growing embryo in a process termed angiogenesis . These new vessels form in response to hypoxic tissues that release hypoxia-inducible factor 1α (HIF 1α) as well as VEGF, which ultimately lead to a stable vascular network. Capillary networks then remodel into arterial, capillary, and venous systems as determined by the surrounding environment. In contrast with vasculogenesis, angiogenesis occurs during embryogenesis as well as during adult life when it provides sprouting to bring blood to ischemic tissue.

Veins and arteries are vessels whose direction of blood flow is either toward (veins) or away from (arteries) the heart, but vessel identity is established prior to blood flow. Arterial and venous differentiation is determined early in the developmental process through cell surface markers including Eph-B2 and Eph-B4. Briefly, arterial differentiation occurs as a result of VEGF binding to the VEGF receptor 2 (VEGF-R2). This leads to Notch activation and suppression of chicken ovalbumin upstream promoter transcription factor II (COUP-TFII), which result in Eph-B2 expression. Venous differentiation is driven by COUP-TFII, which suppresses Notch and results in Eph-B4 expression on endothelial cell surfaces. Lymphatic development occurs as a result of Sox18 and prospero homeobox transcription factor 1 (PROX1). PROX1 forms a heterodimer with COUP-TFII, which leads to expression of VEGF receptor 3 (VEGF-R3) and subsequent lymphatic development.

Early Angiogenesis

As major vascular structures including the heart, dorsal aortas, umbilical vessels, vitelline vessels, and cardinal veins are being formed by vasculogenesis, the embryo is already beginning to remodel the vascular system by the processes of angiogenesis and vascular intussusception. Factors related to the heart and dorsal aortas have a profound effect on the configuration of the vascular system. By day 20, the growth of the neural tube forces the cardiogenic area ventrally and caudally to its final position in the thoracic region, whereas lateral folding of the embryo causes the two endocardial tubes to fuse along the midline, resulting in a single endocardial tube with a more cranially placed outflow and a more caudally located inflow region. As the developing heart lengthens, a series of swellings become visible. Beginning at the inflow end, these include the sinus venosus with its right and left horns, primitive atrium, primitive left ventricle, bulbus cordis (future right ventricle), and truncus arteriosus. The aortic sac, the rostral dilation of the truncus arteriosus, connects the developing heart to the dorsal aortas. Between days 22 and 24, the developing heart moves into its ventral position, and the attached dorsal aortas are forced into a dorsoventral bend that forms the first aortic arch. The first aortic arch is contained in the thickened mesoderm of the developing first pharyngeal arch surrounding the pharynx. Aortic arches two through six develop from mesenchyme within their own pharyngeal arches in a rostral to caudal sequence between days 26 and 30. Lateral folding of the embryo also forces the paired dorsal aortas, beginning at the fourth thoracic somite, to fuse with one another as a common aorta; however, rostral to this level, the dorsal aortas remain as separate vessels. By the beginning of the fourth week, intersegmental vessels between each somite arise from the dorsal aortas. Each intersegmental vessel has a dorsal branch, a lateral branch, and a ventral branch that supplies the individual somite regions.

Aortic Arch

Normal Arch Development

The aortic arch is formed by six pairs of arteries that branch from the ventrally positioned aortic sac to the two dorsal aortas. Diagrammatic representation of these changes would suggest that the aortic arches are all present at the same time, but in reality, the first arches are already regressing while others are still developing. The right horn of the aortic sac forms the brachiocephalic (innominate) artery, right common carotid, and origin of the right subclavian arteries. The left horn of the aortic sac forms the initial portion of the aortic arch.

The first two aortic arches appear and regress quickly and contribute very little to adult structures, whereas the fifth aortic arch never develops in humans ( Fig. 2.2A ). The third aortic arches become the common and proximal segments of the internal carotid arteries. The distal segments of the internal carotid arteries are derived from the dorsal aorta between the first and third arches. The external carotid arteries sprout from the common carotid arteries. The dorsal aorta on each side of the embryo between the third and fourth arches disappears, thus directing blood through the third aortic arch system to the head and neck regions ( Fig. 2.2B ). The fourth aortic arches are asymmetrical with regard to their fate. The left aortic arch forms the part of the adult aortic arch between the left common carotid and left subclavian arteries, whereas the right aortic arch becomes the proximal segment of the right subclavian artery. The remainder of the right subclavian artery is derived from the right dorsal aorta and its right seventh intersegmental artery. The right dorsal aorta distal to the seventh intersegmental artery and proximal to the fused common aorta involutes ( Fig. 2.2C ). The proximal portions of both sixth arches become the right and left pulmonary arteries. The distal segment of the right sixth arch disappears, but the distal segment of the left sixth arch becomes the ductus arteriosus during fetal life and atrophies after birth to become the ligamentum arteriosum ( Fig. 2.2D ).

Aortic Arch Anomalies

In light of the complexity of events that must occur for normal development of the aortic arch and its branches, anomalies do occur. Anomalies result when segments of the primitive aortic arch that should disappear persist, or vice versa. Variations in the development of vessels as they arise from the aortic arch are relatively common, with a “normal” developmental pattern occurring in about 65% of the population, as illustrated in Figure 2.2D . In 15%–30% of the population, the left common carotid artery originates from the brachiocephalic trunk rather than from the aortic arch in what is termed a “bovine arch”. ^, In this case, the brachiocephalic trunk gives rise to the right subclavian, right common carotid, and left common carotid arteries, whereas the left subclavian artery originates from the aortic arch as normally expected, and accounts for 73% of all arch anomalies. Many other variations, each occurring in less than 3% of the population, have been described. Some of these anomalies include a shortened brachiocephalic trunk that bifurcates immediately into the right subclavian and right common carotid arteries, with the left common carotid arising from the aortic arch at the base of the brachiocephalic trunk and a normal origin for the left subclavian artery from the aortic arch. The left vertebral artery can originate directly from the aortic arch between the left common carotid and left subclavian arteries. A left brachiocephalic trunk may be present, which bifurcates into left subclavian and left common carotid arteries.

Patent ductus arteriosus

The ductus arteriosus develops from the distal portion of the left sixth aortic arch and is responsible for shunting blood from the immature, developing fetal lungs to the systemic circulation. A patent ductus arteriosus is the most common vascular anomaly, with an increased incidence in children who are born prematurely. At birth, the ductus normally closes in response to increased oxygen tension and a decrease in prostaglandin production with lung expansion and function. By the age of 1 month, the ductus normally obliterates to become the ligamentum arteriosum. If the ductus arteriosus does not constrict and remains patent, blood is shunted from the high-pressure thoracic aorta to the low-pressure pulmonary system, eventually resulting in significant pulmonary hypertension.

Coarctation of the aorta

Coarctation is a congenital narrowing that can occur at any level of the aorta. The most common location is just distal to the ligamentum arteriosum, and is termed postductal; the preductal type occurs immediately proximal to the ligamentum arteriosum ( Fig. 2.3 ). The etiologic mechanisms related to coarctation remain undefined, however, they are thought to resemble those processes that result in normal, physiologic obliteration of the ductus arteriosus. Oxygen-sensitive muscle tissue from the ductus arteriosus is incorporated into the wall of the aorta. This smooth muscle, which constricts when exposed to high oxygen tension, results in narrowing of the aorta. Eventually chronic changes develop, and the constriction becomes permanent. In the preductal type, the ductus arteriosus remains patent to maintain distal perfusion. In the postductal type, collateral vessels including the internal thoracic, anterior spinal, and intercostal arteries provide perfusion to the lower body. Radiographically, notching on the inferior aspect of the third to eighth ribs may be seen as a consequence of the increased collateral blood flow in the intercostal arteries. ^{, ,}

Double aortic arch

The right dorsal aorta distal to the right seventh intersegmental artery may fail to involute, resulting in a double aortic arch. This segment passes posterior to the esophagus and joins the left aortic arch, which passes anterior to the trachea. As a result, a vascular ring forms around the esophagus and trachea. Symptoms may develop secondary to compression of the esophagus and/or trachea ( Fig. 2.4 ).

Right aortic arch

Involution of the left dorsal aorta distal to the left seventh segmental artery with persistence of the right dorsal aorta (opposite the normal sequence) creates a right aortic arch ( Fig. 2.5 ). The ligamentum arteriosum arises from the distal right sixth arch instead of the distal left sixth arch, but still connects to the aorta. If the arch passes to the left side and posterior to the esophagus, a vascular ring is formed with the ligamentum arteriosum and is known as a right aortic arch with an aberrant left subclavian artery or a retroesophageal component. If the right aortic arch passes anterior to the esophagus and trachea, a vascular ring is not formed, and this is considered a right aortic arch with mirror image branching. The former anomaly may initially be a double aortic arch in which the left dorsal aorta later regresses. The latter is a mirror image of normal anatomy and is associated with a higher incidence of congenital heart malformations, including tetralogy of Fallot.

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