Impact of hemodynamics on efferocytosis in endothelial cells

血流动力学对内皮细胞胞吞作用的影响

• 批准号: 10416262
• 负责人: Zufeng Ding
• 金额: $ 34.2万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10416262
• 关键词: Acute; Address; Adhesions; Affect; Apoptotic; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Blood; Blood Vessels; Blood flow; CRISPR-mediated transcriptional activation; CRISPR/Cas technology; Cardiovascular system; Cell Line; Cells; Cessation of life; Chemicals; Chronic; Clinical; Coagulation Process; Common Femoral Artery; Common iliac artery structure; Complex; Coronary artery; Data; Dendritic Cells; Descending aorta; Development; Diet; Disease; Drug Design; Endothelial Cells; Endothelium; Environment; Epithelial Cells; Event; Exposure to; Failure; Fibrin; Fibroblasts; Flow Cytometry; Friction; Functional disorder; Geometry; Goals; Growth; High Fat Diet; Human; Impairment; In Vitro; Inflammation; Knock-out; Lead; Leukocytes; Ligation; Link; Lipids; Low Density Lipoprotein Receptor; Mechanics; Mediating; Mesenchymal; Modeling; Mus; Myocardial Ischemia; NADPH Oxidase; Necrosis; Pathogenesis; Pattern; Phagocytes; Phenotype; Physiological; Plasmids; Play; Prevention; Process; Production; Protein S; Regulation; Research; Role; Rotation; Rupture; Stroke; Stromal Cells; Surface; Testing; Tissues; Vascular Diseases; Vascular Endothelial Cell; Vascular Permeabilities; Western Blotting; aortic arch; ascending aorta; base; conditional knockout; endothelial dysfunction; hemodynamics; innovation; loss of function; macrophage; mechanical stimulus; mechanotransduction; member; mouse model; neutrophil cytosol factor 40K; neutrophil cytosol factor 67K; novel; novel therapeutic intervention; oxygen transport; prevent; receptor; response; sensor; shear stress; single-cell RNA sequencing; thrombotic; treatment strategy

PROJECT SUMMARY/ABSTRACT Flowing blood generates a frictional force called shear stress that plays an important role in endothelial dysfunction and atherosclerosis. Branches and bends of arteries are exposed to low and disturbed flow (d-flow), a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress generated from steady laminar flow (s-flow) is protective. Helical flow (h-flow) associated with advanced shear stress exists not only in the ascending aorta but also in other parts such as the right coronary artery, descending aorta, common iliac artery, and common femoral artery. H-flow may have several positive physiological roles, such as suppressing/eliminating areas of flow stagnation, preventing the accumulation of atherogenic lipids on the luminal surfaces of arteries, and enhancing oxygen transport from the blood to the arterial wall. Endothelial cells (ECs) are critical sensors of the shear stress that contributes to atherosclerosis. Efferocytosis is a process by which apoptotic tissue is recognized for engulfment by phagocytic cells, such as professional phagocytes (e.g., macrophages and immature dendritic cells) and non-professional phagocytes (e.g., ECs, epithelial cells, fibroblasts, and some stromal cells). Defective efferocytosis in macrophages promotes advanced atherosclerosis. However, the mechanisms by which shear stress environments regulate EC efferocytosis and its implications in atherosclerosis remain largely unknown. The central hypothesis to be tested in this project is that blood flow patterns regulate EC efferocytosis and subsequent endothelial dysfunction and contribute to the development of atherosclerosis. Our long-term goal is to dissect the relationship between blood flow patterns and EC efferocytosis and its role in the development of atherosclerosis. Our specific aims are Aim 1- Define the role of blood flow patterns in EC efferocytosis and endothelial dysfunction, Aim 2- Determine the role of MerTK in endothelial mechanotransduction, and Aim 3- Evaluate the contribution of EC efferocytosis in atherosclerosis. Defining the mechanisms of efferocytosis regulation will be necessary to target endothelial mechanotransduction and subsequent endothelial dysfunction. The proposed research is innovative in the sense that we will connect blood flow patterns, EC efferocytosis, and endothelial mechanotransduction. We will also evaluate the novel mechanism of EC efferocytosis and its contribution to atherosclerosis.

项目总结/摘要 流动的血液产生一种称为剪切应力的摩擦力，该摩擦力在内皮细胞中起重要作用。 功能障碍和动脉粥样硬化。动脉的分支和弯曲暴露于低和扰动流（d流）， 机械环境，促进血管功能障碍和动脉粥样硬化。相反，生理上 由稳定层流（S流）产生的高剪切应力是保护性的。螺旋流（h流）， 先进的剪切应力不仅存在于升主动脉，而且还存在于其他部位，如右冠状动脉 动脉、降主动脉、髂总动脉和股总动脉。H-flow可能有几个积极的 生理作用，如抑制/消除流动停滞区域，防止 在动脉的管腔表面上的致动脉粥样硬化脂质，并增强从血液到动脉的氧运输。 动脉壁内皮细胞（EC）是动脉粥样硬化的剪切应力的关键传感器。 胞吐作用是一种过程，通过该过程，凋亡组织被吞噬细胞（如 专职吞噬细胞（例如，巨噬细胞和未成熟树突细胞）和非专职吞噬细胞 (e.g., EC、上皮细胞、成纤维细胞和一些基质细胞）。巨噬细胞中的缺陷性红细胞增多促进 晚期动脉粥样硬化然而，剪切应力环境调节EC的机制 红细胞增多症及其在动脉粥样硬化中的意义仍不清楚。待检验的中心假设 在这个项目中，血流模式调节EC红细胞增多和随后内皮功能障碍， 导致动脉粥样硬化的发展。我们的长远目标是解剖血缘关系 流动模式和EC胞浆细胞增多及其在动脉粥样硬化发展中的作用。我们的具体目标是 1-确定血流模式在EC红细胞增多症和内皮功能障碍中的作用，目的2-确定 MerTK在内皮机械转导中的作用，目的3-评价EC胞浆细胞增多在内皮细胞机械转导中的作用。 动脉粥样硬化明确红细胞调节的机制对于靶向内皮细胞是必要的。 机械传导和随后的内皮功能障碍。这项研究在某种意义上是创新的 我们将把血流模式、EC胞浆细胞增多和内皮机械传导联系起来。我们还将 评价EC胞浆增多的新机制及其在动脉粥样硬化中的作用。