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。 组织工程结构中的血管，但这些合成的微环境不会导致稳定 持久的血管网络。这是呈现最好的井的一个特别的问题 其特征为血管生成生长因子、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。根据已公布的和初步的数据，我们发现 血管内皮生长因子配体在组织工程支架中的呈递方式不仅影响其物理稳定性，而且 生长因子的释放动力学，以及传递给驻留细胞的分子信号和 最终形成的血管网络形态和成熟度较高。在这项提案中，我们想要 进一步研究血管内皮生长因子配体的呈现如何影响VR-2的磷酸化和由此产生的细胞 结果(表型和血管形态)在体外和体内。目标1和目标2研究血管内皮生长因子 血管内皮生长因子和整合素配体之间的配体提呈和协同信号调节血管内皮生长因子的激活 受体-2(VR-2)、下游信号转导和内皮细胞分支。目标3使用所获得的知识 从目标1和目标2到设计用于中风后脑血管重建的水凝胶支架。

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.