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WIREs Dev Biol
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Understanding vascular development

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Abstract The vasculature of an organism has the daunting task of connecting all the organ systems to nourish tissue and sustain life. This complex network of vessels and associated cells must maintain blood flow, but constantly adapt to acute and chronic changes within tissues. While the vasculature has been studied for over a century, we are just beginning to understand the processes that regulate its formation and how genetic hierarchies are influenced by mechanical and metabolic cues to refine vessel structure and optimize efficiency. As we gain insights into the developmental mechanisms, it is clear that the processes that regulate blood vessel development can also enable the adult to adapt to changes in tissues that can be elicited by exercise, aging, injury, or pathology. Thus, research in vessel development has provided tremendous insights into therapies for vascular diseases and disorders, cancer interventions, wound repair and tissue engineering, and in turn, these models have clearly impacted our understanding of development. Here we provide an overview of the development of the vascular system, highlighting several areas of active investigation and key questions that remain to be answered. WIREs Dev Biol 2013, 2:327–346. doi: 10.1002/wdev.91 For further resources related to this article, please visit the WIREs website.

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The vascular plexus, mechanisms of angiogenesis and the remodeled vasculature. The vascular/capillary plexus, composed of an interwoven capillary network with intervening avascular spaces, and in which the presumptive arterial (red) and venous (blue) sides have been specified, is primarily generated by vasculogenesis. Various mechanisms of angiogenesis—fusion, intussusception, sprouting, and regression—contribute to changes in vessel diameter and vessel density. Remodeling of the plexus results in the formation of a hierarchical vasculature tree with large diameter arteries and veins that are connected to progressively smaller diameter/distal capillaries. Simultaneously, vessels become stabilized by the recruitment of mural cells (pericytes and smooth muscle cells) (tan).

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Variability in vessel morphology and function. Differences in vessel bed morphology, induced by organ‐specific patterning, are easily discernible. Vessels of the adult mouse cerebral cortex show a tree‐like pattern that maximizes blood flow to all of the cells in the brain (a). Vessels of the adult mouse heart are organized in a manner that aligns with the cardiomyocytes (b). Finally, vessels in the adult mouse kidney show a convoluted vascular structure (c).

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Vessel maturation. New vessels (created during remodeling and angiogenesis) begin maturation by the recruitment of differentiating mural cells (pericytes and smooth muscle cells). For example, differentiating smooth muscle cells (SMC precursors) migrate toward a gradient of PDGFB (released from endothelial cells) resulting in activation of PDGFB receptors on SMC precursors (a). Upon the close proximity of SMC precursors to endothelial cells, SMC precursor‐released ANGPT1 induces TEK activation on endothelial cells, which enhances SMC‐endothelial adhesion. Simultaneously, the close proximity of these cells allows for latent TGFB1 (released by both cell types) to become activated. This induces proliferation arrest (quiescence) in SMC precursors and endothelial cells, and induces differentiation of SMCs, yielding vessel stability (b). When a new remodeling or angiogenic mechanism is enacted, competition of ANGPT2 with ANGPT1 for the TEK receptor can disrupt the endothelial‐SMC interaction (c).

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Lymphangiogenesis. During development, lymphatic vessels form from veins. Veins entirely expressing Nr2f2 (blue and orange cells) exhibit a subpopulation of cells that also express Sox18 (orange cells). The coexpression of Nr2f2 and Sox18 confers expression of Prox1 (yellow cells). Prox1 expressing cells migrate away from the vein and downregulate Sox18 (green cells). These cells then connect to one another to form the lymphatic sac, which ultimately forms the lymphatic vasculature.

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The stages of sprouting angiogenesis. Sprouting angiogenesis occurs in stages. (1) Signaling to induce new vessel formation: VEGFA is secreted from tissues, resulting in KDR activation in nearby vessels. (2) Induction of a tip cell: an endothelial cell exposed to the highest concentration of VEGFA becomes a tip cell and exhibits the highest expression of DLL4. (3) Formation of stalk cells: in turn, the tip cell induces NOTCH activation in the juxtaposed neighboring cells to induce stalk cell fate. (4) Vessel outgrowth: stalk cells release soluble FLT1, which functions to bind available VEGFA in the vicinity. This increases the steepness of the VEGFA gradient, and stalk cell proliferation and tip cell pulling drives vessel outgrowth perpendicular to the length of the vessel. (5) Vessel fusion to other vessels: as the vessel grows toward VEGFA, release of VEGFC from macrophages (gray cell) activates FLT4 on endothelial tip cells to guide opposing tip cells together, to promote the conversion of tip cells to stalk cells, and to complete vessel anastamosis.

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Vertebrate Organogenesis > Musculoskeletal and Vascular