The long-term goal of this competitive renewal is to understand the mechanistic basis of the cellular interactions required for vessel formation in the central nervous system (CMS). The CMSvasculature differs from the non-CNS vasculature by the presence of the blood-brain barrier (BBB), the formation of which is largely due to interactions with astrocytes. In the past period of support, we have investigated the role that astrocytes play in orchestrating the events that guide proper cerebral vessel development. In particular, we have identified a mechanism for the astrocytic integrin m/p8 in regulating endothelial differentiation. Thus, we have found that astrocytic av(J8-mediatedactivation of TGF-p inhibits endothelial migration and dramatically alters the expression of major endothelial angiogenic and proteolytic factors. This data fills a previous gap in knowledge of the molecular basis for the reciprocal signaling between astrocytes and endothelial cells. Our data suggests that paracrine TGF-p signaling between astrocytes and endothelial cells is the mechanistic basis for the cerebral hemorrhagic phenotype of integrin p8 subunit knock-out mice. TGF-p is essential to normal CNS vasculogenesis since loss of function of the endothelial receptors for active TGF-p, endoglin and Alk-1, lead to hereditary hemorrhagic telangectasia (HHT) in humans and a similar cerebral hemorrhagic disorder in deficient mice. Because TGF-p is ubiquitously expressed in tissues almost entirely in an inactive (latent) state, the avpS-dependent conversion of latent to active TGF-p by astrocytes could be a major regulatory step in the presentation of active TGF-p to CNS endothelial cells. Our preliminary data demonstrate that astrocytes in brain arteriovenous malformation (BAVM) tissues express less P8than control brain tissues;reduced b8 expression is associated with a b8 genotype associated with AVM susceptibility. Furthermore, we have determined that 08 expression in normal astrocytes is dramatically upregulated by IL-10, and that two SNPs in the IL-10 promoter are associated with BAVMsusceptibility and reduced IL-1 ft expression in a cohort of BA VMpatients. These data suggest several mechanisms whereby J38transcription is reduced in BAVMs. We have recently isolated the human and mouse p8 promoters and have identified an IL-1p responsive region. In addition, we have identifiedseveral tag SNPs mapping near the (38 promoter region that show a strong association (p=0.005) with BAVM susceptibility and correlate with reduced expression of (38expression in perivascular cells in BAVM tissue. Finally, we have determined that conditional deletion ofitgbQ in the brain leads to dysplastic neoangiogenesis in response to local VEGF stimulation. Thus, our novel findings support the hypothesis: Decreased astrocytic P8 expression results in reduced avpS-dependent activation of TGF-p causing pathologic alterations of cerebral vascular integrity and differentiation. This hypothesis will beexplored in three
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