The development and stabilization of the vasculature are complex processes orchestrated by the action of a number of growth factors and a variety of intercellular interactions. The goal of the proposed studies is to characterize the cellular and molecular mechanisms that underlie retinal microvascular growth control and stability in vivo. The studies described in this application test the hypothesis that paracrine interactions between endothelial cells (EC) and pericytes govern the formation and maturation of the retinal microvasculature. To assess the role of TGFB-1 and angl in retinal vessel development and stability in vivo we will use a genetic appoach. Mice will be generated in which a dominant negative (DN) TGF6RII can be inducibly expressed in the endothelium or the SMC/pericytes, and DN Tie2 can be induced in the endothelium. The effect of blocking endothelial or pericyte TGFIS signaling, or endothelial Tie2 during murine retinal vessel development and in the adult vasculature will be assessed. Vessel integrity and permeability as well as endothelial and pericyte proliferation and apoptosis will be examined. The role of VEGF and PIGF in the integrity of the neural and vascular retina will be assessed using a mouse model of circulating soluble Flt1 or soluble Flk1. This model mimics the disease pre-eclampsia, in which elevated soluble Fltt leads to a variety of changes, including proteinuria, hypertension, kidney damage, vision disturbances and eventually seizures. The changes in vision associated with pre-eclampsia have historically been thought to be secondary to hypertension, but we suspect that they are the direct result of VEGF and PIGF neutralization. Systemic and local administration of adenoviruses encoding soluble Flt1 or Flk1 will lead to high circualting levels of these proteins. Preliminary data are presented that indicate alteration in retinal vessel morphology in rodent with elevated sFltl for ten days. The importance of understanding the mechanisms that regulate vessel stability is highlighted by the damage that occurs to the retina, and hence visual acuity, when vessel integrity is breached. Thus, information obtained from these studies is directly relevant to the prevention and treatment of retinopathies and maculopathies.
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