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Mechanisms and Consequences of oxLDL induced endothelial cell stiffening.

机译:oxLDL诱导内皮细胞变硬的机制和后果。

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摘要

Endothelial biomechanics is emerging as a key player in the regulation of vascular endothelial cells. Here, we address the mechanism of endothelial stiffening induced by oxidized-LDL (oxLDL), a potential determinant of cardiovascular disease. We also investigate the role of oxLDL-induced endothelial stiffening in lumen formation. Endothelial stiffness was estimated by analyzing progressive membrane deformation using Micropipette Aspiration. We show that oxLDL induces RhoA activation and that oxLDL-induced endothelial stiffening is abrogated by inhibition of RhoA or its downstream target ROCK. 7-ketocholesterol, a major oxysterol in oxLDL increases endothelial cell stiffening, contractility and network formation. OxLDL-induced increase in endothelial force generation estimated in a gel contraction assay also required RhoA/ROCK activity. OxLDL also facilitates formation of endothelial branching networks in 3D collagen gels in vitro and induces increased formation of functional blood vessels in a Matrigel plug assay in vivo. Both effects are RhoA and ROCK dependent. Importantly, loading cells with cholesterol prevented oxLDL-induced RhoA activation and the downstream signaling cascade and reversed oxLDL-induced lumen formation. The observed effects on oxLDL-induced endothelial stiffening and its association with increased endothelial angiogenic activity in vitro and formation of functional vessels in vivo suggest a potential role for endothelial biomechanics in cardiovascular disease.
机译:内皮生物力学正在成为调节血管内皮细胞的关键因素。在这里,我们解决了由氧化的低密度脂蛋白(oxLDL),心血管疾病的潜在决定因素诱导的内皮硬化的机制。我们还调查了oxLDL诱导的血管内膜形成中的内皮硬化的作用。通过使用微量移液器分析渐进膜变形来估计内皮硬度。我们显示oxLDL诱导RhoA激活,并且通过抑制RhoA或其下游目标ROCK废除oxLDL诱导的内皮硬化。 7-酮胆固醇是oxLDL中的主要氧固醇,可增加内皮细胞的僵硬,收缩性和网络形成。在凝胶收缩试验中,OxLDL诱导的内皮力产生增加也需要RhoA / ROCK活性。 OxLDL还在体外促进3D胶原蛋白凝胶中内皮分支网络的形成,并在体内Matrigel栓塞测定法中诱导功能性血管形成的增加。两种效应均取决于RhoA和ROCK。重要的是,用胆固醇加载细胞可防止oxLDL诱导的RhoA激活和下游信号传导级联,并逆转oxLDL诱导的管腔形成。观察到的对oxLDL诱导的内皮硬化的影响及其与体外内皮血管生成活性的增强和体内功能性血管的形成相关,提示内皮生物力学在心血管疾病中的潜在作用。

著录项

  • 作者

    Oh, Myung-Jin.;

  • 作者单位

    University of Illinois at Chicago.;

  • 授予单位 University of Illinois at Chicago.;
  • 学科 Pharmacology.;Biophysics.;Biochemistry.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 108 p.
  • 总页数 108
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 遥感技术;
  • 关键词

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