Astrocytic integrins in cerebral vessel formation

这种竞争性更新的长期目标是理解机制基础 中枢神经系统(CMS)中血管形成所需的细胞相互作用。 中枢神经系统的血管系统与非中枢神经系统的血管系统的不同之处在于血-脑的存在 屏障(BBB)，其形成很大程度上是由于与星形胶质细胞的相互作用。在过去 在支持期间，我们研究了星形胶质细胞在组织事件中所起的作用 引导脑血管的正常发育。特别是，我们已经确定了一种机制 对于星形细胞整合素m/p8在调节内皮分化中的作用。因此，我们发现， 星形细胞av(J8-介导的转化生长因子-p的激活抑制内皮细胞迁移和显著 改变主要的内皮血管生成和蛋白分解因子的表达。此数据填充一个 以前对相互作用信号的分子基础的认识的差距 星形胶质细胞和内皮细胞。我们的数据表明旁分泌的转化生长因子-β信号在 星形胶质细胞和内皮细胞是脑出血表型的机制基础 整合素p8亚单位基因敲除小鼠。转化生长因子-β对正常的中枢神经系统血管生成是必不可少的，因为 内皮细胞活性转化生长因子-β受体、endoglin和ALK-1功能丧失，导致 遗传性出血性延髓扩张症(HHT)与类似的脑出血 缺陷小鼠的紊乱。因为转化生长因子-β在组织中普遍表达，几乎完全在 非活性(潜伏)状态，星形胶质细胞依赖AVP将潜伏的转化生长因子-β转化为活性转化因子-β 可能是向中枢神经系统内皮细胞呈递活性转化生长因子-β的重要调控步骤。 我们的初步数据表明，脑动静脉畸形(BAVM)中的星形胶质细胞 与对照脑组织相比，脑组织中P8的表达减少；B8的表达减少与 B8基因与动静脉畸形易感性相关。此外，我们已经确定08 IL-10显著上调正常星形胶质细胞的表达，而在星形胶质细胞中的两个SNPs IL-10启动子与BAM易感性和IL-1 ft表达降低相关 BA VM患者队列。这些数据表明J38转录是通过几种机制 减少了BAVM。我们最近分离了人和小鼠的p8启动子，并已经 确定了一个IL-1p反应区域。此外，我们还确定了几个标记SNP的映射 在(38)启动子区域附近，显示出与脑动静脉畸形易感性强相关(p=0.005) 并与脑动静脉畸形组织中血管周围细胞中(38)的表达降低有关。 最后，我们已经确定，大脑中itgbq的有条件缺失会导致发育异常。 局部血管内皮生长因子刺激后的新生血管生成。因此，我们的新发现支持 假设：星形胶质细胞P8表达减少导致AVP依赖性减少 转化生长因子-β的激活引起脑血管完整性的病理改变 差异化。这一假说将分三部分进行探讨。

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