Impact of hemodynamics on efferocytosis in endothelial cells

项目摘要/摘要 流动的血液会产生一种名为剪切力的摩擦力，这种摩擦力在内皮细胞中起着重要作用 功能障碍和动脉粥样硬化。动脉的分支和弯曲暴露在低和扰动的血流(d-血流)中， 促进血管功能障碍和动脉粥样硬化的机械环境。相反，从生理上讲 稳定层流(S流)产生的高剪应力是保护性的。螺旋流(h-流)与 高级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可能有几个正值 生理作用，如抑制/消除流动停滞区域，防止积聚 动脉管腔表面的致动脉粥样硬化脂质，并加强氧气从血液到血管的运输 动脉壁。内皮细胞(ECs)是导致动脉粥样硬化的切应力的关键传感器。 效应细胞吞噬是一个过程，通过这个过程，凋亡组织被吞噬的吞噬细胞识别，例如 专业吞噬细胞(如巨噬细胞和未成熟树突状细胞)和非专业吞噬细胞 (例如，内皮细胞、上皮细胞、成纤维细胞和一些基质细胞)。巨噬细胞有缺陷的泡泡吞噬作用促进 晚期动脉粥样硬化。然而，剪应力环境调节EC的机制 泡泡吞噬作用及其在动脉粥样硬化中的意义在很大程度上仍不清楚。需要检验的中心假说 在这个项目中，血流模式调节EC的胞吐作用和随后的内皮功能障碍 有助于动脉粥样硬化的发展。我们的长期目标是剖析血液和血液之间的关系 血流模式和EC胞吐作用及其在动脉粥样硬化发展中的作用。我们的具体目标就是目标 1-确定血流模式在EC胞吐和内皮功能障碍中的作用，目标2-确定 MerTK在内皮细胞机械转导中的作用和目的3-评估EC在血管内皮细胞吞噬中的作用 动脉硬化。为了靶向内皮，有必要明确吞噬作用的调节机制。 机械转导和随后的内皮功能障碍。本研究具有一定的创新性。 我们将把血流模式、EC胞吐作用和内皮细胞机械转导联系起来。我们还将 评价EC胞吐作用的新机制及其在动脉粥样硬化中的作用。

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.