VEGF Ligand Presentation and Therapeutic Angiogenesis

人们普遍认为，人工合成的微环境可以促进血液的形成 组织工程结构内的血管，但这些合成的微环境不会导致稳定的 血管网络是持久的。这是一个特别的问题，介绍了最好的 特征性血管生成因子，血管内皮生长因子（VEGF）。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 为治疗性血管生成设计支架。根据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其物理稳定性， 生长因子的释放动力学，以及传递到驻留细胞的分子信号， 最终形成形态和成熟的维管网络。在这份提案中，我们希望 进一步研究VEGF配体的表达如何影响VR-2的磷酸化， 体外和体内结果（表型和血管形态）。Aim 1和Aim 2研究了VEGF VEGF和整联蛋白配体之间的配体呈递和协同信号传导调节VEGF活化 受体-2（VR-2）、下游信号传导和内皮细胞分支。目标3使用获得的知识 目的1和2设计水凝胶支架用于中风后脑血管重建。

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 proposal, 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.