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首页> 外文期刊>International Journal of Cell Biology >Extracellular Vesicles from Caveolin-Enriched Microdomains Regulate Hyaluronan-Mediated Sustained Vascular Integrity
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Extracellular Vesicles from Caveolin-Enriched Microdomains Regulate Hyaluronan-Mediated Sustained Vascular Integrity

机译：来自富含空洞蛋白的微区的细胞外囊泡调节透明质酸介导的持续血管完整性。

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Defects in vascular integrity are an initiating factor in several disease processes.We have previously reported that high molecular weight hyaluronan (HMW-HA), a major glycosaminoglycan in the body, promotes rapid signal transduction in human pulmonary microvascular endothelial cells (HPMVEC) leading to barrier enhancement. In contrast, low molecular weight hyaluronan (LMWHA), produced in disease states by hyaluronidases and reactive oxygen species (ROS), induces HPMVEC barrier disruption. However, the mechanism(s) of sustained barrier regulation by HA are poorly defined. Our results indicate that long-term (6– 24 hours) exposure of HMW-HA induced release of a novel type of extracellular vesicle from HLMVEC called enlargeosomes (characterized by AHNAK expression) while LMW-HA long-term exposure promoted release of exosomes (characterized by CD9, CD63, and CD81 expression). These effects were blocked by inhibiting caveolin-enriched microdomain (CEM) formation. Further, inhibiting enlargeosome release by annexin II siRNA attenuated the sustained barrier enhancing effects of HMW-HA. Finally, exposure of isolated enlargeosomes to HPMVEC monolayers generated barrier enhancement while exosomes led to barrier disruption. Taken together, these results suggest that differential release of extracellular vesicles from CEM modulate the sustained HPMVEC barrier regulation by HMW-HA and LMW-HA. HMW-HA-induced specialized enlargeosomes can be a potential therapeutic strategy for diseases involving impaired vascular integrity.
机译：血管完整性缺陷是多种疾病过程的起始因素。我们先前曾报道过高分子量透明质酸（HMW-HA）是人体内主要的糖胺聚糖，可促进人肺微血管内皮细胞（HPMVEC）的快速信号转导，从而导致屏障增强。相反，由透明质酸酶和活性氧（ROS）在疾病状态下产生的低分子量透明质酸（LMWHA）会诱导HPMVEC屏障破坏。但是，医管局对可持续屏障进行调节的机制尚不明确。我们的结果表明，长期（6-24小时）暴露于HMW-HA会导致从HLMVEC释放出一种新型的胞外囊泡，称为膨大体（以AHNAK表达为特征），而LMW-HA长期暴露会促进外泌体的释放（ （以CD9，CD63和CD81表达为特征）。这些作用被抑制，丰富了抑制caveolin的微域（CEM）的形成。此外，通过膜联蛋白II siRNA抑制放大体释放减弱了HMW-HA的持续屏障增强作用。最后，将分离的扩增小体暴露于HPMVEC单层可增强屏障，而外泌体则导致屏障破坏。综上所述，这些结果表明从CEM的细胞外囊泡的不同释放调节了HMW-HA和LMW-HA对HPMVEC的持续屏障调节。 HMW-HA诱导的特化扩增体可能是涉及血管完整性受损的疾病的潜在治疗策略。

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