VEGF Ligand Presentation and Therapeutic Angiogenesis

描述（由申请人提供）：人们普遍认为，在组织工程构建体中，可以设计合成微环境来促进血管的形成，但这些合成微环境不能产生持久稳定的血管网络。血管内皮生长因子（VEGF）是最具特征的血管生成生长因子，这是一个特别的问题。我们的长期目标是获得对工程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。基于已发表的和初步的数据，我们发现VEGF配体在组织工程支架中的呈递方法不仅影响生长因子的物理稳定性和释放动力学，而且影响传递给驻留细胞的分子信号，最终影响形成的血管网络的形态和成熟度。在这个应用中，我们想进一步研究VEGF配体呈递如何在体外和体内影响VR-2磷酸化和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VEGF配体的呈递和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）的激活、下游信号传导和内皮细胞分支。Aims 3利用Aims 1和Aims 2中获得的知识设计脑卒中后脑血运重建的水凝胶支架！

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.