Endogenous Regulation of Angiogenesis in Vitro

Abstract

Rings of rat aorta embedded in collagen gel and cultured under serum-free conditions produce a self-limited angiogenic response in the absence of exogenous growth factors. Aortic rings respond to the injury of the dissection procedure by generating outgrowths of branching microvessels and fibroblasts. The microvessels originate primarily from the aortic intima whereas fibroblasts arise from the adventitia. The endothelium of the rat aorta switches to a microvascular phenotype and recruits pericytes from a subpopulation of smooth muscle cells located in the intimal/subintimal layers. Formation of microvessels is due to the combined effect of injury, exposure of the apical surface of the endothelium to a hydrated collagen matrix, and paracrine interactions between endothelial and nonendothelial cells. Endogenous growth factors involved in the regulation o angiogenesis include basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF). and platelet-derived growth factor (PDGF). bFGF and VEGF stimulate angiogenesis directly. PDGF stimulates fibroblasts and pericytes, which in turn modulate the growth, differentiation and survival of microvessels. Fibroblasts, which are the first cells to migrate out of the expiants, promote angiogenesis by secreting growth factors and by stabilizing the newly formed microvessels. Pericytes, which increase in number during the maturation of the microvessels, contribute to the differentiation and remodeling of the neovasculature. These results indicate that the rat aorta model can be used to study the cellular and molecular mechanisms by which the vessel wall regulates microvessel formation at different stages of the angiogenic process.