首页研究心血管 › Circ Res: 血管平滑肌细胞的钙化是通过调节外泌体分泌介导的

Circ Res: 血管平滑肌细胞的钙化是通过调节外泌体分泌介导的

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血管平滑肌细胞(VSMC)分泌的细胞外膜泡形成了矿化作用的第一个病灶,fetuin-A作为一个钙化作用的抑制分子被装载在细胞外膜泡中。然而,fetuin-A被包裹在细胞外膜泡中在细胞间传递的过程尚不清楚。来自伦敦国王学院的研究者们阐明了细胞外膜泡在VSMC的钙化过程中的作用。Alexa488标记的fetuin-A被VSMC获取,通过胞内体系统,从多泡小体中以外泌体的形式分泌出去。VSMC来源的外泌体同样富含CD9\CD63和CD81,并且其分泌受鞘磷脂磷酸二酯酶3的调节。比较蛋白质组学显示VSMC来源的外泌体的成分与其他细胞来源的外泌体相似,且与成骨细胞来源的外泌体一样都含有钙离子结合蛋白和细胞外基质蛋白。在体外,细胞外钙浓度的提高会诱导鞘磷脂磷酸二酯酶3的表达,促进钙化外泌体的分泌。抑制鞘磷脂磷酸二酯酶3可抑制VSMC的钙化。在体内,从透析的慢性肾脏疾病的病人样本中观察到了多泡小体中的外泌体,CD63与钙化共定位。重要的是,在钙化的条件下,TNF-α和PDGF-BB也可以提高外泌体的生成,从而增强了VSMCs的钙化。该研究证明了在应对外界改压力是相关因子可促进外泌体的分泌,从而促进血管的钙化。通过调节外泌体的分泌可能成为一个新的治疗靶点。

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原文来源:Alexander N. Kapustin,et.al. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ Res. 2015; 116: 1312-1323.

Rationale: Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs. However, the processes of fetuin-A intracellular trafficking and MV biogenesis are poorly understood.

Objective: The objective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification.

Methods and Results: Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via the endosomal system, and exocytosed from multivesicular bodies via exosome release. VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated by sphingomyelin phosphodiesterase 3. Comparative proteomics showed that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources but also shared components with osteoblast-derived MVs including calcium-binding and extracellular matrix proteins. Elevated extracellular calcium was found to induce sphingomyelin phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin phosphodiesterase 3 prevented VSMC calcification. In vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize with calcification. Importantly, factors such as tumor necrosis factor-α and platelet derived growth factor-BB were also found to increase exosome production, leading to increased calcification of VSMCs in response to calcifying conditions.

Conclusions: This study identifies MVs as exosomes and shows that factors that can increase exosome release can promote vascular calcification in response to environmental calcium stress. Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.

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外泌体资讯网 Circ Res: 血管平滑肌细胞的钙化是通过调节外泌体分泌介导的

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