Neurotrophins in angiogenesis

描述（由申请人提供）： 血管生成是一种生理过程，其中新血管形成以满足血管的生长。 局部组织的氧合需求。因此，特异性促进血管生成的生长因子的鉴定将提供改善动脉粥样硬化闭塞动脉系统的缺血后果的手段。尽管VEGF和bFGF等因子在临床前试验中似乎很有希望，但人体研究结果却参差不齐，这促使人们寻找具有血管生成活性的其他因子。在这里，我们建议研究的神经营养因子之一，BDNF，在促进缺血心脏和骨骼肌侧支血管形成的作用。最为人所知的是神经元的分化和存活因子，我们最近通过对BDNF无效突变小鼠的分析，将BDNF确定为心脏血管稳定和存活的关键调节因子。此外，BDNF在非缺血性动物模型中抑制血管生成作用。虽然我们的长期目标是确定BDNF是否可以促进缺血性人类心肌血管形成，我们提出了三个相互关联的目标，以确定BDNF促进血管生长和血管功能不全的动物模型的稳定性的机制。首先，我们将确定BDNF对纯化的微血管内皮细胞的作用，评估趋化性，增殖和存活，并将表征 调节这些事件的信号通路。其次，我们将研究组织缺血时BDNF的诱导，并鉴定上调BDNF的细胞类型。最后，我们将在充分表征的后肢缺血和冠状动脉狭窄模型中表征对BDNF单独或与VEGF组合的血管生成反应，以评估对毛细血管形成、血管平滑肌细胞对血管的包鞘和血管重塑的影响。这些研究将使我们能够确定骨骼肌或心肌细胞局部产生的脑源性神经营养因子是否促进缺血组织中的血管生长。此外，这些研究将测试BDNF是否与VEGF协同作用以促进新形成血管的稳定性。

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.