Neurotrophins in angiogenesis

描述(由申请人提供)： 血管生成是一个生理过程，在这个过程中，新的血管形成，以满足 局部组织的氧合需求。因此，识别特异性促进血管生成的生长因子将为改善动脉系统闭塞的动脉粥样硬化的缺血后果提供一种手段。尽管像血管内皮生长因子和碱性成纤维细胞生长因子这样的因子在临床前试验中看起来很有希望，但在人类身上的研究是混合的，促使人们寻找更多具有血管生成活性的因子。在这里，我们建议研究一种神经营养因子，BDNF，在促进缺血心脏和骨骼肌侧支血管形成方面的作用。作为神经元的分化和存活因子，我们最近通过对BDNF缺失突变小鼠的分析，发现BDNF是心脏血管稳定和存活的关键调节因子。此外，脑源性神经营养因子抑制非缺血动物模型的血管生成作用。虽然我们的长期目标是确定BDNF是否能促进人类缺血心肌中血管的形成，但我们提出了三个相互关联的目标，以确定在血管功能不全的动物模型中BDNF促进血管生长和稳定性的机制。首先，我们将确定bdnf对纯化的微血管内皮细胞的作用，评估其趋化、增殖和存活，并将表征 调节这些事件的信号通路。其次，我们将研究脑源性神经营养因子在组织缺血反应中的诱导，并鉴定上调脑源性神经营养因子的细胞类型。最后，我们将在典型的后肢缺血和冠脉狭窄模型中，研究BDNF单独或联合血管生成因子的血管生成反应，以评估对毛细血管形成、血管平滑肌细胞包裹血管和血管重塑的影响。这些研究将使我们能够确定骨骼或心肌细胞局部产生的BDNF是否促进了缺血组织中的血管生长。此外，这些研究将测试BDNF是否与血管内皮生长因子协同作用，以促进新形成的血管的稳定性。

DESCRIPTION (provided by applicant): Angiogenesis is a physiological process in which new blood vessels are formed to meet the oxygenation demands of local tissues. Thus, the identification of growth factors which specifically promote angiogenesis would provide a means to ameliorate the ischemic consequences of atherosclerosis occluding the arterial system. Although factors such as VEGF and bFGF appeared promising in pre-clinical trials, studies in humans have been mixed, prompting a search for additional factors with angiogenic activity. Here we propose to study the role of one of the neurotrophins, BDNF, in promoting collateral vessel formation in the ischemic heart and skeletal muscle. Best known as a differentiative and survival factor for neurons, we have recently identified BDNF as a critical regulator of cardiac vessel stabilization and survival through analysis of BDNF null mutant mice. In addition, BDNF inhibits angiogenic actions in nonischemic animal models. Although our long term goals are to determine whether BDNF can promote vessel formation in ischemic human myocardium, we propose three interrelated aims to identify the mechanisms by which BDNF promotes vessel growth and stability in animal models of vascular insufficiency. First, we will identify the actions of BDNF on purified microvascular endothelial cells, assessing chemotaxis, proliferation and survival, and will characterize the signaling pathways which regulate these events. Second, we will study the induction of BDNF in response to tissue ischemia, and identify the cell types which upregulate BDNF. Lastly, we will characterize the angiogenic response to BDNF, alone or in combination with VEGF in the well characterized models of hindlimb ischemia and coronary constriction to assess effects on capillary formation, ensheathment of vessels by vascular smooth muscle cells and vascular remodeling. These studies will allow us to determine whether local production of BDNF by skeletal or cardiac myocytes promotes vessel growth in ischemic tissue. In addition, these studies will test whether BDNF acts coordinately with VEGF to promote the stability of newly formed vessels.