Osteopontin and Collateral Vessel Growth

描述（由申请人提供）：为缺血组织提供血流的新侧支血管的发展是一个极其复杂的过程，它发生在几个不同的过程中，包括从现有血管结构中产生新血管，骨髓来源的内皮前体细胞向缺血部位迁移，炎症细胞的募集，内皮通道（既有和新形成的）与血管平滑肌细胞的动脉化。虽然人们对生长因子如VEGF和bFGF的参与已经了解了很多，但适应性血管生长的精确分子机制非常复杂，仍然不完全清楚。分泌的磷蛋白骨桥蛋白被认为是骨重塑的调节剂，在目前的研究中被认为在修复性血管生成中具有潜在的作用。支持骨桥蛋白在血管生长中的可能作用的间接证据来自几个来源，包括骨桥蛋白支持细胞迁移、阻止内皮细胞凋亡和促进平滑肌细胞生长的观察。此外，骨桥蛋白是1v21-3整合素的配体，在细胞存活和新生血管形成中起重要作用。这些数据得到了骨桥蛋白缺乏（OPN-/-）小鼠伤口愈合（可能涉及血管生成的过程）受损的观察结果的支持。此外，最近的研究利用转染的分泌高水平骨桥蛋白的小鼠神经母细胞瘤细胞表明，骨桥蛋白可以促进局部血管生成并促进肿瘤生长。也有研究表明骨桥蛋白的表达与胃癌、乳腺癌和肺癌的进展有关。相反，骨桥蛋白缺乏已被证明可减少实验性肿瘤细胞向骨和软组织的转移，并减少因血管化减少而继发的植入异位骨的吸收。我们最近的研究表明，骨桥蛋白积极调节血管炎症过程，这表明骨桥蛋白可以增强成人新生血管的另一个重要机制。基于这些间接数据，我们假设骨桥蛋白在出生后血管生长中起关键作用。我们建议利用骨桥蛋白缺陷小鼠来确定骨桥蛋白在新血管形成中的功能作用，并进一步确定炎症反应对这一过程的贡献。公共卫生相关性：成人新生血管的发育是一种重要的机制，通过这种机制，成人可以补偿动脉粥样硬化引起的血管阻塞。这项工作将研究骨桥蛋白，一种被认为在调节这一过程中非常重要的重要蛋白质。最终目标是开发更好的治疗方法来治疗动脉粥样硬化患者。

DESCRIPTION (provided by applicant): The development of new collateral blood vessels to provide blood flow to ischemic tissue is an extremely complex process that occurs as a result of several distinct processes including sprouting of new blood vessels from existing vascular structures, migration of bone marrow-derived endothelial precursor cells to sites of ischemia, recruitment of inflammatory cells, and arterialization of endothelial channels (both existing and newly formed) with vascular smooth muscle cells. While much has been learned about the involvement of growth factors such as VEGF and bFGF the precise molecular mechanisms underlying adaptive vascular growth are extremely complex and remain incompletely understood. The secreted phosphoprotein osteopontin, well known as a modulator of bone remodeling, is being considered in the present study for its potential role in reparative angiogenesis. Circumstantial evidence supporting a possible role for osteopontin in vascular growth comes from several sources including the observations that osteopontin supports cell migration, prevents apoptosis of endothelial cells and is growth promoting for smooth muscle cells. In addition, osteopontin is a ligand for 1v21-3 integrins which are known to be important in cell survival and neovascularization. These data are supported by the observations that wound healing (a process that may involve angiogenesis) is impaired in osteopontin deficient (OPN-/-) mice. Furthermore, recent studies employing transfected murine neuroblastoma cells secreting high levels of osteopontin show that osteopontin enhances local angiogenesis and promotes tumor growth. It has also been shown that expression of osteopontin correlates with progression of gastric, breast and lung cancers. Conversely, osteopontin deficiency has been shown to reduce experimental tumor cell metastasis to bone and soft tissues and to reduce resorption of implanted ectopic bone secondary to reduced vascularization. We have recently shown that osteopontin positively modulates vascular inflammatory processes which suggest an additional important mechanism through which osteopontin can enhance neovascularization in the adult. Based on these circumstantial data, we hypothesize that osteopontin plays a pivotal role in postnatal vascular growth. We propose to make use of osteopontin deficient mice to define the functional role of osteopontin in new vessel formation and to further define the contributions of inflammatory responses to this process. PUBLIC HEALTH RELEVANCE: The development of new blood vessels in the adult is an important mechanism through which the adult can compensate for blockages in blood vessels that are caused by atherosclerosis. This work will study osteopontin, an important protein that is thought to be very important in regulating this process. The ultimate goal is to develop better therapeutic approaches to treating patients with atherosclerosis.