VEGF Ligand Presentation and Therapeutic Angiogenesis

描述（由申请人提供）：公认的是，合成微环境可以被工程化以促进组织工程化构建体内血管的形成，但是这些合成微环境不会产生持久的稳定血管网络。这一直是一个特殊的问题，介绍了最好的特点血管生成生长因子，血管内皮生长因子（VEGF）。我们的长期目标是获得工程血管微环境的分子理解，并利用这些信息更好地设计治疗性血管生成的支架。基于已发表的和初步的数据，我们已经发现，在组织工程支架中VEGF配体呈递的方法不仅影响生长因子的物理稳定性和释放动力学，而且影响传递到驻留细胞的分子信号，并最终影响所形成的血管网络的形态和成熟度。在本申请中，我们希望进一步研究VEGF配体呈递如何影响VR-2磷酸化以及由此产生的体外和体内细胞结果（表型和血管形态）。目的1和目的2研究VEGF配体呈递和VEGF与整合素配体之间的协同信号传导如何调节VEGF受体-2（VR-2）的活化、下游信号传导和内皮细胞分支。目标3使用从目标1和2中获得的知识来设计用于中风后脑血管重建的水凝胶支架！ 公共卫生相关性：治疗性血管生成旨在修复缺乏正常血液供应的受损组织。本申请旨在更好地了解血管内皮生长因子（VEGF）和细胞外基质蛋白如何能够诱导血管形成，以更好地设计用于治疗性血管生成的支架。

DESCRIPTION (provided by applicant): It is well accepted that synthetic microenvironments can be engineered to promote the formation of blood vessels within tissue-engineered constructs, but that these synthetic microenvironments do not result in stable vascular networks that are long lasting. This has been a particular problem with presentation of the most well characterized angiogenic growth factor, vascular endothelial growth factor (VEGF). Our long-term goal is to gain a molecular understanding of engineered vascular microenvironments and to use this information to better design scaffolds for therapeutic angiogenesis. Based on published and preliminary data we have found that the method of VEGF ligand presentation in tissue engineering scaffolds affects not only the physical stability and release kinetics of the growth factor, but also the molecular signals conveyed to the residing cells and ultimately the morphology and maturity of the resulting vascular network formed. In this application, we want to further investigate how VEGF ligand presentation affects VR-2 phosphorylation and the resulting cellular outcomes (phenotype and vessel morphology) in vitro and in vivo. Aim 1 and Aim 2 investigate how VEGF ligand presentation and synergistic signaling between VEGF and integrin ligands modulate activation of VEGF receptor-2 (VR-2), downstream signaling and endothelial cell branching. Aim 3 uses the knowledge gained from Aims 1 and 2 to design hydrogel scaffolds for revascularization of the brain after stroke! PUBLIC HEALTH RELEVANCE: Therapeutic angiogenesis aims to repair damaged tissue that lacks a normal blood supply. This application aims to better understand how vascular endothelial growth factor (VEGF) and extracellular matrix proteins are able to induce blood vessel formation to better design scaffolds for therapeutic angiogenesis.