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7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment
Angiogenesis ( IF 9.2 ) Pub Date : 2021-02-28 , DOI: 10.1007/s10456-021-09770-0
Haibo Wang 1 , Aniket Ramshekar 1 , Eric Kunz 1 , M Elizabeth Hartnett 1
Affiliation  

Oxidized cholesterols and lipids accumulate in Bruch’s membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroidal endothelial cell (CEC) migration and macular neovascularization in AMD. Compared to control, 7KC injection caused 40% larger lectin-stained lesions, but 70% larger lesions measured by optical coherence tomography one week after laser-injury. At two weeks, 7KC-injected eyes had 86% larger alpha smooth muscle actin (αSMA)-labeled lesions and more collagen-labeling than control. There was no difference in cell death. 7KC-treated RPE/choroids had increased αSMA but decreased VE-cadherin. Compared to control-treated CECs, 7KC unexpectedly reduced endothelial VE-cadherin, CD31 and VEGFR2 and increased αSMA, fibroblast activation protein (FAP) and transforming growth factor beta (TGFβ). Inhibition of TGFβ receptor-mediated signaling by SB431542 abrogated 7KC-induced loss of endothelial and increase in mesenchymal proteins in association with decreased transcription factor, SMAD3. Knockdown of SMAD3 partially inhibited 7KC-mediated loss of endothelial proteins and increase in αSMA and FAP. Compared to control, 7KC-treatment of CECs increased Rac1GTP and migration, and both were inhibited by the Rac1 inhibitor; however, CECs treated with 7KC had reduced tube formation. These findings suggest that 7KC, which increases in AMD and with age, induces mesenchymal transition in CECs making them invasive and migratory, and causing fibrosis in macular neovascularization. Further studies to interfere with this process may reduce fibrosis and improve responsiveness to anti-VEGF treatment in non-responsive macular neovascularization in AMD.



中文翻译:

7-酮胆固醇诱导内皮-间质转化并促进纤维化:对新生血管性年龄相关性黄斑变性和治疗的影响

在年龄相关性黄斑变性 (AMD) 中,氧化的胆固醇和脂质在布鲁赫膜中积累。目前尚不清楚这些物质与 AMD 病理生理学之间存在什么因果关系。我们提出了一个假设,即一种流行的形式,7-酮胆固醇 (7KC),促进 AMD 中的脉络膜内皮细胞 (CEC) 迁移和黄斑新生血管形成。与对照相比,7KC 注射引起的凝集素染色病变增大 40%,但激光损伤一周后通过光学相干断层扫描测量的病变增大 70%。两周后,注射 7KC 的眼睛比对照组的 α 平滑肌肌动蛋白 (αSMA) 标记病变大 86%,胶原蛋白标记更多。细胞死亡没有差异。7KC 处理的 RPE/脉络膜增加了 αSMA 但减少了 VE-钙粘蛋白。与对照处理的 CEC 相比,7KC 出人意料地减少了内皮 VE-钙粘蛋白、CD31 和 VEGFR2,并增加了 αSMA、成纤维细胞活化蛋白 (FAP) 和转化生长因子 β (TGFβ)。SB431542 对 TGFβ 受体介导的信号传导的抑制消除了 7KC 诱导的内皮细胞丢失和与转录因子 SMAD3 减少相关的间充质蛋白增加。SMAD3 的敲低部分抑制了 7KC 介导的内皮蛋白丢失和 αSMA 和 FAP 的增加。与对照相比,CEC 的 7KC 处理增加了 Rac1GTP 和迁移,并且两者都被 Rac1 抑制剂抑制;然而,用 7KC 处理的 CEC 减少了管的形成。这些发现表明,随着 AMD 和年龄的增长,7KC 会诱导 CEC 中的间充质转化,使其具有侵袭性和迁移性,并导致黄斑新生血管形成纤维化。

更新日期:2021-03-01
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