Autocrine Mechanisms of Angiogenesis

我们广泛的前期工作产生了一个意想不到的假设，即已经确立的凋亡基因可能是一种新的基因。 转化生长因子-β 1（TGF-β 1）对内皮细胞的作用是由内源性 血管内皮生长因子（VEGF）。这一结论是基于我们的发现，TGF-β 1刺激 内皮细胞VEGF表达和VEGF单克隆抗体阻断TGF-β 1诱导的 凋亡由于细胞凋亡是血管形成的重要组成部分，因此， 内皮细胞凋亡可能在血管生成和血管发生中起重要作用。因此我们 建议： 1.表征VEGF受体和下游信号通路，通过其内源性 VEGF介导TGF-β 1对内皮细胞的凋亡活性。我们将研究信号传导 响应于TGF-bl处理，内源性VEGF激活的途径，以及潜在的串扰 VEGF-和TGF-β 1-特异性途径之间的联系。使用合成抑制剂和显性阴性 突变体将提供鉴定介导TGF-β 1凋亡信号的信号传导途径。 2.研究VEGF介导的细胞凋亡在体内外血管生成中的作用。 TGF-β 1诱导细胞凋亡和血管形成。根据我们的初步工作，我们假设， TGF-β 1的血管生成和血管生成活性由VEGF以自分泌机制介导。 我们建议使用血管生成和血管生成的体外和体内模型来测试我们的假设。 这些结果将阐明血管形成是由以下因素的相互作用控制的机制： VEGF和TGF-bl，两种有效的血管生成诱导剂。详细了解的机制，通过 VEGF和TGF-β 1相互作用对药物治疗的发展具有重要意义。 旨在控制血管生成的治疗。

Our extensive preliminary work has generated the unexpected hypothesis that the well-established apoptotic effect of transforming growth factor-beta 1 (TGF-bl) on endothelial cells is mediated by endogenous vascular endothelial growth factor (VEGF). This conclusion is based on our findings that TGF-bl stimulates endothelial cell expression of VEGF and that monoclonal antibodies to VEGF block TGF-bl-induced apoptosis. Because apoptosis is an essential component of vessel formation, this novel mechanism of endothelial cell apoptosis may have an important role in angiogenesis and vasculogenesis. We therefore propose: 1. To characterize the VEGF receptor(s) and downstream signaling pathways through which endogenous VEGF mediates the apoptotic activity of TGF-bl on endothelial cells. We will investigate signal transduction pathways activated by endogenous VEGF in response to TGF-bl treatment, and potential cross-talk between VEGF- and TGF-bl-specific pathways. The use of synthetic inhibitors and dominant negative mutants will afford to identify the signaling pathway(s) that mediate TGF-bl apoptotic signal(s). 2. To study the role of VEGF-mediated apoptosis in angiogenesis and vasculogenesis in vitro and in vivo. TGF-bl induces both apoptosis and vessel formation. Based on our preliminary work, we hypothesize that the angiogenic and vasculogenic activities of TGF-bl are mediated by VEGF with an autocrine mechanism. We propose to test our hypothesis using in vitro and vivo models of angiogenesis and vasculogenesis. The results will elucidate the mechanisms through which vessel formation is controlled by the interplay of VEGF and TGF-bl, two potent angiogenesis inducers. A detailed understanding of the mechanisms through which VEGF and TGF-bl interact can have important implications for the development of pharmacological treatments aimed to control angiogenesis.