Osteopontin and Collateral Vessel Growth

描述(申请人提供)：发展新的侧支血管为缺血组织提供血流是一个极其复杂的过程，它是几个不同过程的结果，包括从现有的血管结构中长出新的血管，骨髓来源的内皮前体细胞迁移到缺血部位，炎细胞的募集，以及与血管平滑肌细胞的内皮通道(包括现有的和新形成的)的动脉化。虽然对生长因子如血管内皮生长因子和碱性成纤维细胞生长因子的参与已经了解很多，但支持适应性血管生长的确切的分子机制是极其复杂的，仍然不完全清楚。分泌型磷蛋白骨桥蛋白被认为是骨重建的调节剂，目前正在考虑其在修复性血管生成中的潜在作用。支持骨桥蛋白在血管生长中可能作用的间接证据来自几个来源，包括观察到骨桥蛋白支持细胞迁移，防止内皮细胞凋亡，并促进平滑肌细胞的生长。此外，骨桥蛋白是1v21-3整合素的配体，整合素在细胞存活和新生血管中起重要作用。这些数据被观察到骨桥蛋白缺陷(OPN-/-)小鼠的伤口愈合(一个可能涉及血管生成的过程)受损所支持。此外，最近利用高水平分泌骨桥蛋白的转基因小鼠神经母细胞瘤细胞的研究表明，骨桥蛋白促进局部血管生成，促进肿瘤生长。研究还表明，骨桥蛋白的表达与胃癌、乳腺癌和肺癌的进展有关。相反，骨桥蛋白缺乏被证明可以减少实验性肿瘤细胞对骨和软组织的转移，并减少继发于血管生成减少的异位骨的吸收。我们最近发现骨桥蛋白正向调节血管炎症过程，这表明骨桥蛋白可以通过另一个重要的机制促进成人的新生血管形成。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乏的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在这一过程中的作用。公共卫生相关性：成人新血管的发育是成人补偿动脉粥样硬化引起的血管阻塞的重要机制。这项工作将研究骨桥蛋白，这是一种重要的蛋白质，被认为在调节这一过程中非常重要。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.