Elucidating the role of pericytes in angiogenesis in the brain using a tissue-engineered microvessel model

点击翻译按钮获取中文摘要

Project Summary Angiogenesis is a complex and tightly regulated process essential for tissue repair in response to injury or disease. In the adult human brain, the cerebrovasculature is largely quiescent but angiogenesis is associated with disease (e.g. stroke, neurodegenerative disease, and brain cancer), wound healing (e.g. traumatic brain injury), and physiological factors (e.g. exercise, high altitude adaptation, etc.). In the generally accepted model of brain angiogenesis, when blood vessels are exposed to angiogenic cues, pericytes detach from activated endothelial cells and are passive bystanders during sprout formation and growth, only migrating back to surround the newly formed endothelium in the maturation phase. However, a few studies in humans and animal models have reported that pericytes can play an active role in angiogenesis, leading sprout growth and promoting the migration of stalk cells. The objective of this project is to identify the role of pericytes during angiogenesis in the brain. Our major hypothesis is that pericytes can be selectively activated to become the tip cells and lead the growth of angiogenic sprouts. The objective will be addressed in three aims. In Aim 1, we will use a tissue-engineered post-capillary venule model to assess the role of hypoxia and growth factor gradients on pericyte-guided angiogenesis. In Aim 2, we will evaluate the transcriptomic profile of pericytes during angiogenesis. Immunostaining and in situ RNA hybridization will be used to examine key markers of tip cells as well as to validate key sequencing results. In Aim 3, we will perform a proof-of-concept experiment to test the hypothesis that gene editing can be used to engineer tip cell phenotype. Understanding the role of pericytes in adult brain angiogenesis is important in understanding the response to the cerebrovasculature to a wide range of perturbations and will enable the development of new therapies for cerebrovascular repair.