The long-term goal of this proposal is to understand the regulation of vessel stability in the central nervous system (CNS). Towards this goal, we will investigate the mechanisms underlying cellular interactions required for stable vessel formation in the CNS. Specifically, we will investigate the cell-type specific roles that integrins play in CNS vessel stabilization. For CNS vessels to become fully competent, interactions of endothelial ceils with other cell types are required. The CNS vasculature is distinct from other vascular beds because of selective permeability properties (blood-brain-barrier). These properties are due to paracrine interactions between astrocytes and endothelial cells, the basis of which are poorly understood. We have previously determined that a cell-adhesion receptor, integrin avb8, recently identified as being essential for normal murine cerebral vascular development, is expressed by astrocytes and not by endothelial cells or smooth muscle cells. Integrin b8 subunit knock-out mice die at late gestation of cerebral hemorrhage providing the first genetic evidence to support a role for astrocytes in cerebral vascular development/stabilization. We hypothesize that action of astrocytic avb8 on endothelial cells is paracrine in nature since our preliminary data suggests that that avb8 is the major molecular mediator of TGF-b activation in cultured astrocytes. TGF-b is likely candidate molecule to provide instructional cues and to orchestrate proliferation and differentiation events between astrocytes and endothelial cells; loss of function of the endothelial receptors for active TGF-b, endoglin and Alk-1, lead to the development of brain arteriovenous malformations in humans (HHT-1 and 2). Because TGF-b is ubiquitously expressed in tissues almost entirely in an inactive (latent) state, the avb8-dependent conversion of latent to active TGF-b by astrocytes could be a major regulatory step in the presentation of active TGF-b to CNS endothelial cells. Thus, our novel findings support the hypothesis: astrocytic integrin mediated conversion of latent to active TGF-b is essential for the development and stabilization of a normal cerebral vasculature. This wilt be tested in three specific aims: 1) To test the hypothesis that astrocytes regulate the activity of TGF-b. 2) To test the hypothesis that astrocytic integrins modify endothelial function, in vitro. 3) To test the hypothesis that the integrin-mediated release of TGF-b by astrocytes plays a role in cerebral vessel formation/stabilization, in vivo. These studies will provide mechanistic insight into the reciprocal interactions between endothelial cells and astrocytes, which may lead to the development of novel therapeutics targeted at the treatment of brain vascular malformations, stroke and cerebral edema.
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