VEGF Ligand Presentation and Therapeutic Angiogenesis

描述(申请人提供)：公认的是，合成微环境可以通过工程来促进组织工程构建物中血管的形成，但这些合成微环境不会导致稳定的、持久的血管网络。这是一个特别的问题，因为最具特征的血管生成生长因子，血管内皮生长因子(血管内皮生长因子)。我们的长期目标是获得工程化血管微环境的分子理解，并利用这些信息更好地设计用于治疗性血管生成的支架。根据已发表的和初步的数据，我们发现组织工程支架中血管内皮生长因子配体的呈递方式不仅影响生长因子的物理稳定性和释放动力学，而且还影响传递给驻留细胞的分子信号，最终影响所形成的血管网络的形态和成熟度。在这一应用中，我们希望进一步研究在体外和体内，血管内皮生长因子配体的存在如何影响VR-2的磷酸化以及由此产生的细胞结果(表型和血管形态)。目的1和目的2研究血管内皮生长因子配体的呈递及其与整合素配体之间的协同信号如何调节血管内皮生长因子受体-2(VR-2)的激活、下游信号转导和内皮细胞分支。目标3利用从目标1和目标2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。这一应用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，以便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.