Title: Vascular endothelial growth factor is required for vascular and tissue homeostasis
Description: While the function of VEGF in developmental, physiologic and pathologic angiogenesis is well understood, its role in vascular and tissue homeostasis is unclear. Recent clinical observations, including side-effects from anti-VEGF therapies for cancer, and from the disease preeclampsia, which is mediated in part by an endogenous VEGF inhibitor, have begun to implicate VEGF in the maintenance of adult vasculature. I first determined the expression pattern of VEGF in the adult mice utilizing VEGF-lacZ mice. These analyses revealed that VEGF was expressed in a cell-specific manner in all vascularized tissues examined. The pattern of VEGF expression was consistent with a role for VEGF in the maintenance of fenestrations and in endothelial cell (EC) survival. In addition, I demonstrated that VEGFR2, the main signaling receptor for VEGF, was expressed and activated in the adult. Using tissue culture models, our laboratory has previously demonstrated a role for TGFβ in vessel formation and stability as well as in the regulation of VEGF expression. I therefore investigated the effect of VEGF and TGFβ neutralization, alone and in combination, in adult mice. Systemic neutralization of VEGF and TGFβ in adult mice was accomplished by adenoviral expression of soluble Flt1 (sVEGFR1, sFlt1) and soluble endoglin (sEng). Results of these studies revealed that VEGF neutralization led to reduced vascular perfusion in the choroid plexus (CP). Simultaneous neutralization of VEGF and TGFβ resulted in loss of fenestrations in the CP vasculature.

Further, these studies identified ependymal cells as a non-vascular target; neutralization of VEGF and TGFβ led to the attenuation of ependymal cell cilia. The perturbations in the CP vasculature and ependyma were associated with increased periventricular permeability as observed by MRI. Examination of the potential pathogenesis underlying vessel non-perfusion revealed that VEGF neutralization led to increased leukocyte-endothelial interactions and elevated expression of P-selectin by the endothelium in the absence of leukocyte or platelet activation. In addition, I have participated in investigations into the function of VEGF in the adult retina. VEGF blockage for 14 days had no apparent effect on the vasculature of the inner retina but was associated with major loss of photoreceptor cells, suggesting that VEGF may act as an endogenous neuroprotectant. Taken together, these data provide evidence that VEGF plays an important role in both vascular and non-vascular homeostasis and that manipulation of VEGF levels may lead to systemic vascular and tissue dysfunction.