The vascular system is essential for the transport of oxygen, nutrients and waste to and from tissues. It also has other roles including regulating blood pressure, transporting hormones required for communication between different tissues and transporting cells of the immune system to the site of an immune response. The vascular system is one of the earliest systems to develop and function during vertebrate embryogenesis.
The vascular system is a tree-like network of arteries, veins and capillaries. Blood vessels are made up of endothelial cells, smooth muscle cells, connective tissue and perivascular cells as shown in Figure 1. Vascular development occurs through two processes; vasculogenesis and angiogenesis. Vasculogenesis leads to the formation of the first major embryonic blood vessels and results in formation of the primary vascular plexus in the yolk sac. The yolk sac is a membranous sac attached to the embryo that functions as the developmental circulatory system of the human embryo, before internal circulation begins. Once circulation begins, primary vessels are remodelled into arteries and veins in order to develop a functional, mature vascular system. This is known as angiogenesis.
Vasculogenesis is the de novo formation of blood vessels from endothelial cell precursors known as angioblasts. Angioblasts are generated during the first step of vasculogenesis. Most angioblasts are derived from progressive restriction of mesoderm cells to the endothelial lineage in response to signalling molecules such as IHH (Indian Hedgehog), FGF2 (fibroblast growth factor), BMPs (bone morphogenetic proteins), and VEGF (vascular endothelial growth factor). FGF-2 induces angioblast formation from mesoderm to promote vessel growth. Some endothelial cells may be derived from hemangioblasts; bipotent cells that give rise to both hematopoietic and angioblastic cells, as shown in Figure 2.
Vasculogenesis begins after the initiation of gastrulation in the mammalian embryo. The process begins with the formation of blood islets in the yolk sac and hemangioblasts in the head mesenchyme and posterior lateral plate mesoderm. Angioblastic cells emerge scattered throughout the mesoderm, forming small clumps and then cords which then differentiate into endothelial cells. The cells are connected via intercellular adherence junctions such as gap junctions and tight junctions. The cords gradually acquire lumens and unite to form vessels. Binding of VEGF to VEGFR1 is one of the stimuli involved in tube formation and endothelial cell-cell interactions, resulting in mature vessels in a primary vascular complex.
Once the primary vascular complex has formed, angiogenesis causes vascular remodelling through the sprouting, branching and bridging of existing vessels and the growth of new vessels from existing vessels. This process requires endothelial cells to migrate, proliferate, establish junctions and apical-basal polarity, and deposit a stabilizing basement membrane. VEGF binding to VEGFR1 and 2 is one of the signals involved in causing this pruning and remodelling. VEGF is a key molecule required for vascular development, demonstrated by the fact that VEGF null mice can’t form blood vessels.
Branching of vessels during angiogenesis requires different endothelial cells to respond differently to common signals. For sprouting to occur, one endothelial cell must be selected for outward migration from the existing vessel, this cell is known as the tip cell. The tip cell then responds to a VEGF gradient by migrating up the gradient and away from the original vessel. The endothelial cells behind the tip cell form a sprout emerging from the original vessel. These cells are known as stalk cells and do not migrate independently, but follow the leading tip cell and eventually canalise to form vessels with a lumen. Stalk cells beside the tip cell release soluble VEGFR1, which competitively binds to VEGF in the VEGF gradient. This prevents it from binding to VEGFR1 on stalk cells and so preventing them from responding to this signal and migrating independently. The tip cell must eventually fuse with the target vessel to establish a circuit. After this active sprouting process, endothelial cells become quiescent by adopting a phenotype that promotes vessel integrity and stabilizes the vasculature.
Platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-β stimulate maturation and remodelling of vessels to produce a ‘mature’ vascular system. PDGF binds to PDGFR and TGFβ binds to TGFβR to promote vessel maturation by stimulating smooth muscle cell migration and differentiation. These stimuli work together with artriovenous specification cues to facilitate proper development and enlargement of arteries and veins.
Binding of Angiopoietin1 to its receptor Tie2 causes differentiation, recruitment and interaction of perivascular cells such as pericytes and myofibroblast-like cells. Pericytes are found in close association with capillaries. They are embedded within the basement membrane of capillaries with their dendritic processes penetrating through to the endothelial cells, which have processes projecting back into the pericytes. Pericytes have been suggested to be involved in growth of new capillaries or vessel stability.
A hierarchy of arteries, veins and capillaries is initially established through complementary gene expression of membrane bound ligands and receptors known as Ephrins and Ephs, respectively. Ephrins are membrane bound ligands of which there are two types; type A is GPI linked (being anchored to the membrane by a glycosylphosphatidylinositol (GPI) linkage) and type B is a transmembrane ligand. Ephs are membrane bound receptors from a family of receptor tyrosine kinases which bind either A or B ligands. Binding of Ephs to Ephrins causes bidirectional signalling – each cell stimulates the other on contact. Ephrin B2 is expressed only in arteries and its receptor, EphB4, is expressed only in veins. When ephrin B2 on arterial endothelial cells makes contact with Eph4 on venous endothelial cells, fusion is permitted and angiogenic remodelling occurs. At sites without Eph4 and ephrinb2, fusion is forbidden.
As shown in Figure 3, in Zebrafish the differential expression of Ephrin B2 and Ephb4 is established by Sonic hedgehog (Shh) expression from the notochord, which induces somite VEGF production. VEGF binds to its receptors VEGFR-2 and neuropilin-1, activating the Notch signaling pathway, which upregulates ephrinB2, specifying an artery. Less Notch stimulation in endothelial cells stimulates Ephb4 expression, specifying a vein.
The branching and sprouting of vessels during angiogenesis is not random but involves path finding cues similar to those found in neuronal development, as described in Figures 4 and 5. In fact there is some evidence that nerves are required for the patterning and branching of blood vessels (see Mukouyama et al. 2002). Path-finding in vascular development involves the same signalling molecules as in neural development: Sprouty, Slit, Netrin and Semaphorins.
The lymphatic system transports lymph around the body in order to maintain fluid homeostasis. It also serves as a way of transporting cells of the immune system. The lymphatic vascular system is a highly branched network of capillaries and ducts that is present in most organs and tissues. The lymphatic system is made up of small capillaries which drain into precollecting vessels, then collecting vessels, and then into the thoracic duct or the right lymphatic trunk. Lymph then drains from here into the subclavian veins. Lymphatic vascular development requires transdifferentiation of venous endothelial cells into lymphatic endothelial cells, sprouting and maturation of lymphatic vessels, and separation of blood and lymphatic vasculature.
Lymphatic vessels stem from preexisting blood vessels. Lymphatic endothelial cells (LECs) differentiate from a subset of venous endothelial cells that expresses the transcription factor Prox1. PROX1 specifies lymphatic identity to blood endothelial cells. LECs bud and migrate away from veins to form the first lymphatic structures in regions where VEGF-c is supplied by the lateral mesoderm. In mice, reorganisation of lymphatic vasculature into capillaries, precollectors, and collecting lymphatic vessels starts at E15.5. Foxc2 and NFAT signalling pathways cooperate in establishing collecting lymphatic vessels. The Tie1 and Tie2 endothelial receptor tyrosine kinases also control lymphatic vascular development.
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