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Endothelial Cell Cycle State and Cell Fate

内皮细胞周期状态和细胞命运

基本信息

批准号：
10208947
负责人：
Karen Kemper Hirschi
金额：
$ 52.61万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208947
关键词：
Arteries Blood Circulation Blood Vessels Blood capillaries Blood flow Cardiovascular system Cell Culture System Cell Cycle Cell Cycle Regulation Cell Proliferation Cells Clinical Data Defect Development Ectoderm Embryonic Development Endoderm Endothelial Cells Endothelium Engineering Ensure Evaluation Exhibits G1 Arrest G1 Phase Gene Expression Genes Growth Human In Vitro Maintenance Mesoderm Metabolic Modeling Molecular Mus Natural regeneration Nutrient Oxygen Pathology Phenotype Process Regenerative Medicine Regulation Research Role Signal Pathway Signal Transduction Structure Testing Tissue Engineering Tissues Tube Up-Regulation Vascular remodeling Vascularization Veins Venous Venous Malformation Waste Products arteriole blood vessel development cell growth embryonic stem cell human stem cells in vivo in vivo Model injured injury and repair insight ischemic injury mechanotransduction migration mouse model neovascularization notch protein novel postnatal prevent repaired replacement tissue response restoration shear stress vascular injury vasculogenesis venule

项目摘要

Establishing a functional vascular network is a rate-limiting step in embryonic development, the repair of injured tissues, and the engineering of tissue replacements. Although we have made progress in identifying factors that promote endothelial cell proliferation and sprouting, we lack understanding of how to properly control endothelial cell growth and phenotypic specialization during vascular remodeling, which has created a significant roadblock for clinical therapies, tissue engineering and regenerative medicine. Although multiple signaling pathways have been implicated in the regulation of arterial-venous network formation, including flow-induced mechanotransduction and Notch signaling, the mechanisms by which these signals coordinately regulate endothelial cell growth suppression and identity were unclear. Our recent studies revealed that remodeling vascular plexi are subject to systemic blood circulation, and that shear stress of different magnitudes promotes differential growth responses and gene expression. That is, arterial/arteriolar shear stress levels promote Notch signaling, and downstream p27-induced late G1 phase arrest that enables arterial gene expression (Fang 2017). Conversely, flow magnitudes typical of veins/venules induce early G1 arrest, and enables upregulation of venous genes. Interestingly, distinct endothelial cell cycle states appear to be maintained in arteries vs. veins postnatally. We know very little about the role of cell cycle control in endothelial cell fate decisions, or the differential signaling pathways induced by vessel-specific flow magnitudes, and how they may coordinately induce and maintain endothelial cell cycle state and identity. The scientific premise of our research is that endothelial cell cycle control is required for proper arterial and venous specification, such that when endothelial cells are in different cell cycle states, they exhibit different propensity for arterial vs. venous gene expression. Support for this idea comes from studies in embryonic stem cells that show cells in early vs. late G1 phase have a propensity for mesoderm/endoderm vs. ectoderm fate, respectively (Paulkin 2014). Thus, our hypothesis is that differential flow forces in arteries and veins induce different intracellular signaling pathways that promote distinct endothelial cell cycle states, creating distinct windows of opportunity for the regulation of arterial vs. venous gene expression. To ensure scientific rigor, we will test this hypothesis in vivo in models of arterial- venous network formation and repair, and in vitro in human endothelial cell culture systems that allow flow manipulation. We will define mechanisms by which vessel-specific flow magnitudes modulate endothelial cell cycle state, determine how distinct endothelial cell cycle states enable differential phenotypic specialization (artery vs. vein), and determine whether manipulation of endothelial cell cycle state can prevent or correct arterial-venous malformations and enhance post-injury vascular repair. Evaluation of this hypothesis will yield novel fundamental insights into blood vessel formation and regeneration that can be used to create human microvasculature ex vivo and treat vascular pathologies.

建立功能性血管网络是胚胎发育的限速步骤