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Mechanisms Regulating Vascular Homeostasis

调节血管稳态的机制

基本信息

批准号：
10299286
负责人：
Christopher D Kontos
金额：
$ 59.09万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10299286
关键词：
ANGPT1 gene Address Adhesions Angiopoietins Apolipoprotein E Atherosclerosis Binding Binding Sites Biology Blood Vessels CRISPR/Cas technology Calmodulin Cardiovascular Diseases Cell Survival Cell physiology Cessation of life Co-Immunoprecipitations Coronary heart disease Defect Endothelial Cells Endothelium Event Gene Expression Genetic Genetic Transcription Goals Health Homeostasis Hypertension In Vitro Inflammation Lead Ligands Link Liquid substance Malignant Neoplasms Mediating Modeling Molecular Mus Myography NOS3 gene Nitric Oxide Oxygen Pathologic Neovascularization Perfusion Permeability Phenotype Phosphorylation Play Proteins Public Health Receptor Signaling Recombinant Proteins Regulation Regulatory Pathway Retinal Diseases Role Scaffolding Protein Septic Shock Signal Pathway Signal Transduction Testing Transcription Factor AP-1 Vascular Diseases Vascular Permeabilities Vascular remodeling angiogenesis atheroprotective base cardiovascular disorder prevention density endothelial dysfunction in vivo induced pluripotent stem cell loss of function monocyte mutant novel pressure prevent receptor response rho shear stress transcription factor vascular inflammation western diet

项目摘要

PROJECT SUMMARY Regulation of normal endothelial cell (EC) function plays a critical role in vascular homeostasis and the prevention of cardiovascular disease (CVD). Endothelial dysfunction in CVD is characterized by loss of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO). The Tie receptors and their ligands, the angiopoietins (Ang), are important regulators of vascular homeostasis and the transition from EC quiescence to "activation" and vascular remodeling. Whereas Ang-1/Tie2 signaling promotes EC survival and quiescence, in part through activation of Akt and eNOS, the homologous Tie1 receptor has been shown to promote EC activation, inflammation, and atherosclerosis. However, Tie1 is also required for Tie2-mediated angiogenesis, and Tie1's overall functional effects appear to be context-dependent and linked, in part, to the presence of inflammation. Unlike Tie2, Tie1 has no known activating ligands, therefore its signaling pathways and mechanisms of action have been difficult to study and remain poorly understood. We identified a novel and previously uncharacterized molecular scaffolding protein, Caskin2, as a Tie1-interacting protein. Although few studies have specifically addressed Caskin2's function, it has been identified as a strong marker of ECs, and numerous molecular studies have linked Caskin2 to phenotypes associated with defects in vascular homeostasis. Importantly, our studies indicate that Caskin2 is a critical molecular link between Tie receptor signaling, eNOS biology, and vascular homeostasis. Our preliminary studies in this proposal demonstrate that Caskin2 is highly expressed in ECs in vitro and in vivo and that Caskin2 promotes EC quiescence and survival in vitro. Caskin2 binding to Tie1 is disrupted by phosphorylation of T794 on Tie1, an event that is mediated by PAK in a Rac-dependent manner and that is required for angiogenesis. Moreover, Caskin2 is required for Ang- 1/Tie2-mediated signaling through Akt, suggesting that Caskin2 integrates signals from both Tie1 and Tie2 to regulate vascular homeostasis. Furthermore, Caskin2 binds eNOS and its activator calmodulin (CaM) and increases eNOS expression and activity and is upregulated by fluid shear stress and by KLF2. Finally, we show that Caskin2–/– mice have increased vascular permeability, atherosclerosis, pathological angiogenesis, and are hypertensive, all disorders of vascular homeostasis characterized by abnormal eNOS signaling. Based on these findings, we hypothesize that Caskin2 is a critical integrator of Tie receptor signaling that regulates vascular homeostasis in part through eNOS activation. To test this hypothesis, the Specific Aims of this proposal are to: 1) Determine the molecular mechanisms by which Caskin2 regulates Tie receptor-mediated endothelial function and eNOS activity; 2) Determine the mechanisms by which Caskin2 responds to and senses changes in fluid shear stress to regulate EC phenotypes in vitro; and 3) Determine the effects of Caskin2 deficiency on vascular homeostasis in vivo.

项目总结