Dichotomous role of integrin-β5 in lung endothelial cells.
Dichotomous role of integrin-β5 in lung endothelial cells.
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DOI：
10.1002/pul2.12156
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发表时间：
2022-10
影响因子：
2.6
通讯作者：
Farkas, Laszlo
中科院分区：
文献类型：
--
作者：
Blanchard, Neil;Link, Patrick A.;Farkas, Daniela;Harmon, Brennan;Hudson, Jaylen;Bogamuwa, Srimathi;Piper, Bryce;Authelet, Kayla;Cool, Carlyne D.;Heise, Rebecca L.;Freishtat, Robert;Farkas, Laszlo
肺动脉高压（PAH）是一种进行性、破坏性疾病，其主要组织学表现为闭塞性肺动脉病。PAH的一个重要功能成分是异常的内皮细胞（EC）功能，包括凋亡抵抗、增殖不受抑制和迁移受损。导致和维持生理和异常EC功能的机制尚未完全理解。在这里，我们检验了这样一个假设，即在PAH中，EC的跨膜蛋白整合素-β5表达增加，这有助于在生理和病理条件下的迁移和存活，我们发现PAH患者和慢性缺氧和注射CD 117+诱导的PH大鼠肺动脉病变和肺组织中整合素β5表达升高，大鼠肺EC克隆。这些EC克隆表现出整联蛋白-β5及其异源二聚化伴侣整联蛋白-αν的表达升高，并显示出屏障形成加速。体外抑制整合素-ανβ5部分阻断了转化生长因子（TGF）-β1诱导的大鼠肺对照EC中的EnMT基因表达，而在大鼠肺EC克隆和人肺微血管EC中较少。整联蛋白-ανβ5的抑制促进内皮功能障碍，如通过划痕测定中的迁移减少和与TGF-β1协同作用中的细胞凋亡增加所示。在体内，阻断整联蛋白-ανβ5加重了大鼠中由慢性缺氧和CD 117 + EC克隆诱导的PH。总之，我们发现整合素-ανβ5在肺内皮存活和迁移中的作用，但也对TGF-β1诱导的EnMT基因表达有部分贡献。我们的结果表明，整合素-ανβ5是EC的生理功能和肺血管稳态所必需的。
Pulmonary arterial hypertension (PAH) is a progressive, devastating disease, and its main histological manifestation is an occlusive pulmonary arteriopathy. One important functional component of PAH is aberrant endothelial cell (EC) function including apoptosis‐resistance, unchecked proliferation, and impaired migration. The mechanisms leading to and maintaining physiologic and aberrant EC function are not fully understood. Here, we tested the hypothesis that in PAH, ECs have increased expression of the transmembrane protein integrin‐β5, which contributes to migration and survival under physiologic and pathological conditions, but also to endothelial‐to‐mesenchymal transition (EnMT). We found that elevated integrin‐β5 expression in pulmonary artery lesions and lung tissue from PAH patients and rats with PH induced by chronic hypoxia and injection of CD117+ rat lung EC clones. These EC clones exhibited elevated expression of integrin‐β5 and its heterodimerization partner integrin‐αν and showed accelerated barrier formation. Inhibition of integrin‐ανβ5 in vitro partially blocked transforming growth factor (TGF)‐β1‐induced EnMT gene expression in rat lung control ECs and less in rat lung EC clones and human lung microvascular ECs. Inhibition of integrin‐ανβ5 promoted endothelial dysfunction as shown by reduced migration in a scratch assay and increased apoptosis in synergism with TGF‐β1. In vivo, blocking of integrin‐ανβ5 exaggerated PH induced by chronic hypoxia and CD117+ EC clones in rats. In summary, we found a role for integrin‐ανβ5 in lung endothelial survival and migration, but also a partial contribution to TGF‐β1‐induced EnMT gene expression. Our results suggest that integrin‐ανβ5 is required for physiologic function of ECs and lung vascular homeostasis.
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影响因子：
20.1
作者：
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通讯作者：
RABINOVITCH, M
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通讯作者：
Rabinovitch M