40 - Slits and Netrins in Vascular Patterning: Taking Cues from the Nervous System

Summary

The formation of a functional blood vessel depends on endothelial cell (EC) proliferation and migration, tube formation, and the differentiation and recruitment of vascular smooth muscle cells (VSMCs). Some of the growth factors responsible for vascular development were first identified using cell biological assays that evaluated angiogenic properties. These assays include in vitro EC proliferation, adhesion, and migration assays, and in vivo aortic ring, chorioallantoic membrane (CAM), and corneal micropocket assays. These studies identified vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor (TGF)-β, angiopoietins, platelet-derived growth factor (PDGF), and their homologues and isoforms, in addition to their multiple cognate receptors (1,2).

Gene targeting experiments demonstrated that many of these growth factors and their receptors are essential for vascular development and provided insight into how sprouting is initiated and a mature network is sculpted. VEGF and its receptors play an essential role in EC proliferation and differentiation. The critical requirement for VEGF at the earliest stage of vasculogenesis is demonstrated by the lack of EC development even in Vegf hemizygous mice (3). Once ECs aggregate and undergo tubulogenesis, VSMCs are recruited by PDGF to surround the mature vessel. In the absence of PDGF or its receptors, a subset of vessels fails to recruit VSMCs and pericytes (4). Finally, gene targeting studies have revealed that stabilization and maturation of blood vessels, through the interaction of ECs and VSMCs, is mediated by angiopoietins, TGF-β, and extracellular matrix (ECM) proteins (2). Thus, gene ablation experiments have identified which signaling pathways play essential roles in murine vascular development and have delineated the fundamental blueprint for the sequence of molecular events that govern nascent blood vessel formation.