Antagonism of vascular endothelial growth factor results in microvessel attrition and disorganization of wound tissue

Vascular endothelial growth factor (VEGF) is a potent growth factor that is indispensable for the development of blood vessels in the fetus and for wound healing in adults. VEGF likely plays a role in maintaining the blood vessels once they have been formed. It is not clear, however, whether a low tissue VEGF (caused either by disease or by systemic administration of VEGF antagonists) can cause abnormalities in preexisting blood vessels, especially of wound tissue that requires high local levels of VEGF for healing. The present study investigated the effect of VEGF antagonism on blood vessels of foreign-body granulomas (a model of wound-healing tissue). Granulomas were induced by implanting perforated polyvinyl tubes into the subcutaneous tissue of rats and allowed to develop for 14 days, at which time the implanted tubes were completely encapsulated by the subcutaneous tissue. The encapsulated granulomas consisted of 3 distinct histological layers, of which the middle layer was well perfused by a rich supply of microvessels. Morphologically, the granuloma remained "stable" after developing for 14 days. At 1 week, VEGF levels in the granuloma fluid, which is in equilibrium with the interstitial fluid, were 25 times higher than in the plasma. VEGF levels in the granuloma fluid continued to increase for up to 3 weeks, reflecting the high dependence of the wound tissue on ambient VEGF levels. After injection of the VEGF receptor antagonist in the fully formed granuloma, the preexisting blood vessels in the middle layer regressed and underwent apoptosis, accompanied by expansion of the extracellular matrix (predominately collagen I) into areas normally devoid of matrix. We conclude that wound tissue is sensitive to ambient VEGF levels, and that a low VEGF condition resulting from VEGF receptor antagonism can disrupt the healing of wound tissue.