Modulating Endothelialization of Cardiovascular Grafts

调节心血管移植物的内皮化

• 批准号: 6969959
• 负责人: MICHAEL SOBEL
• 金额: $ 32.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969959
• 关键词: biomaterial development /preparation; biotechnology; blood vessel prosthesis; cell differentiation; cell growth regulation; cell migration; dogs; fibronectins; heparin; laboratory rat; protein binding; protein protein interaction; receptor binding; receptor expression; surface plasmon resonance; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): A durable bioprosthetic vascular graft is badly needed for vascular bypass surgery. For peripheral vascular surgery, there is essentially no viable alternative to an autogenous venous conduit to bypass leg arteries. In part, the challenges to establishing an endothelialized graft have been gaps in our understanding of how specific growth factors and matrix proteins interact with each other and modulate cellular responses. Heparins are known to modulate growth responses, but heparin's effects have been confusing and contradictory, due to the heterogeneity of heparin's structure and its diverse interactions. We have discovered that vascular endothelial growth factor (VEGF) and fibronectin (Fn) have a unique and dedicated biologic partnership. Fn binds VEGF like no other matrix protein, and Fn significantly enhances the endothelial migration and proliferation mediated by VEGF. Their cognate receptors, alpha5beta1 and VEGFR2 also work in synergy. We have also demonstrated that VEGF-Fn complexes uniquely enhance the differentiation of endothelial progenitor cells (EPC) into the endothelial line. Our goals are: 1) Elucidate the mechanisms underlying Fn promotion of VEGF activity, 2) Define the structure-activity relations of heparin's modulation of VEGF-VEGFR2 binding, 3) Define and develop recombinant fibronectin constructs and heparin oligosaccharides that when combined with VEGF and EPC will enhance endothelialization of a porous vascular graft, by capillary in growth and the differentiation of EPC. Using recombinant Fn constructs, we will identify the Fn domains that are key to promoting VEGF mitogenic effects. Using structurally defined synthetic oligosaccharides, and novel surface plasmon resonance technology we will identify the optimal size and structure of heparin that promotes VEGF binding to its receptor VEGFR2. In an animal model of peripheral artery bypass grafting that closely resembles the human condition, we will test these constructs and cells for their ability to promote the growth of a stable endothelial lining.

描述（由申请人提供）：血管搭桥手术急需耐用的生物假体血管移植物。对于外周血管手术，基本上没有可行的替代自体静脉导管来绕过腿部动脉。在某种程度上，建立内皮化移植物的挑战在于我们对特定生长因子和基质蛋白如何相互作用并调节细胞反应的理解存在差距。众所周知，肝素可以调节生长反应，但由于肝素结构的异质性及其相互作用的多样性，肝素的作用一直令人困惑和矛盾。我们已经发现血管内皮生长因子（VEGF）和纤维连接蛋白（Fn）有一个独特的和专用的生物伙伴关系。Fn不像其他基质蛋白那样与VEGF结合，Fn显著增强VEGF介导的内皮细胞迁移和增殖。它们的同源受体，alpha5beta1和VEGFR2也协同工作。我们也证明了VEGF-Fn复合物能够独特地促进内皮祖细胞（EPC）向内皮细胞系的分化。我们的目标是：1)阐明Fn促进VEGF活性的机制；2)确定肝素调节VEGF- vegfr2结合的构效关系；3)确定并开发重组纤维连接蛋白构建物和肝素低聚糖，当它们与VEGF和EPC结合时，将通过毛细血管生长和EPC分化增强多孔血管移植物的内皮化。利用重组Fn结构体，我们将确定促进VEGF有丝分裂作用的Fn结构域。利用结构明确的合成寡糖和新型表面等离子体共振技术，我们将确定促进VEGF与其受体VEGFR2结合的肝素的最佳大小和结构。在一个与人类情况非常相似的外周动脉搭桥移植动物模型中，我们将测试这些构建物和细胞促进稳定内皮细胞生长的能力。