Autocrine Mechanisms of Angiogenesis

描述(申请人提供)：我们广泛的前期工作产生了一个意想不到的假设，即转化生长因子-β1(转化生长因子-β1)对内皮细胞的凋亡效应是由内源性血管内皮生长因子(VEGF)介导的。这一结论是基于我们的研究结果，即转化生长因子-β1刺激内皮细胞表达血管内皮生长因子，并且抗血管内皮生长因子的单抗阻断转化生长因子-β1诱导的细胞凋亡。由于细胞凋亡是血管形成的重要组成部分，这一新的内皮细胞凋亡机制可能在血管生成和血管生成中发挥重要作用。因此，我们提出：1.研究血管内皮生长因子受体(S)及其下游信号通路，探讨内源性血管内皮生长因子介导转化生长因子-β1对内皮细胞的凋亡作用。我们将研究内源性血管内皮细胞生长因子激活的信号转导通路对转化生长因子-β1治疗的反应，以及血管内皮生长因子和转化生长因子-β1特异性信号转导通路之间潜在的相互作用。合成抑制剂和显性负性突变体的使用将为鉴定介导转化生长因子-β1凋亡信号的信号通路(S)提供依据(S)。2.研究血管内皮生长因子介导的细胞凋亡在体内外血管生成和血管生成中的作用。转化生长因子-β1可诱导细胞凋亡和血管形成。在我们前期工作的基础上，我们假设转化生长因子-β1的血管生成和血管生成活性是由血管内皮生长因子以自分泌机制介导的。我们建议使用血管生成和血管生成的体外和体内模型来验证我们的假设。这一结果将阐明血管形成受两种有效的血管生成诱导剂--血管内皮生长因子和转化生长因子-β1相互影响的机制。详细了解血管内皮生长因子和转化生长因子-β1相互作用的机制对于开发旨在控制血管生成的药物治疗具有重要意义。

DESCRIPTION (provided by applicant): Our extensive preliminary work has generated the unexpected hypothesis that the well-established apoptotic effect of transforming growth factor-beta 1 (TGF-b1) on endothelial cells is mediated by endogenous vascular endothelial growth factor (VEGF). This conclusion is based on our findings that TGF-b1 stimulates endothelial cell expression of VEGF and that monoclonal antibodies to VEGF block TGF-b1-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-b1 on endothelial cells. We will investigate signal transduction pathways activated by endogenous VEGF in response to TGF-b1 treatment, and potential cross-talk between VEGF- and TGF-b1-specific pathways. The use of synthetic inhibitors and dominant negative mutants will afford the identification of the signaling pathway(s) that mediate TGF-b1 apoptotic signal(s). 2. To study the role of VEGF-mediated apoptosis in angiogenesis and vasculogenesis in vitro and in vivo. TGF-b1 induces both apoptosis and vessel formation. Based on our preliminary work, we hypothesize that the angiogenic and vasculogenic activities of TGF-b1 are mediated by VEGF with an autocrine mechanism. We propose to test our hypothesis using in vitro and in 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-b1, two potent angiogenesis inducers. A detailed understanding of the mechanisms through which VEGF and TGF-b1 interact can have important implications for the development of pharmacological treatments aimed at the control of angiogenesis.