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.