Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation.
Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation.
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DOI：
10.1161/circresaha.112.300646
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发表时间：
2013-04-26
影响因子：
20.1
通讯作者：
Cornfield DN
中科院分区：
文献类型：
--
作者：
Kim YM;Barnes EA;Alvira CM;Ying L;Reddy S;Cornfield DN
缺氧诱导因子-1α HIF-1α是一种氧（O2）敏感转录因子，介导低氧张力状态的转录反应。急性缺氧可引起肺血管收缩，慢性缺氧可引起血管重构和肺动脉高压，但围绕HIF-1α在调节肺血管张力中的作用存在矛盾的数据。探讨平滑肌细胞（SMC）特异性HIF-1α在调节肺血管张力中的作用。我们建立了SMC特异性缺失HIF-1α (SM22α-HIF-1α - / -)的小鼠，以验证肺动脉平滑肌细胞（PASMC） HIF-1α调节肺血管张力和缺氧反应的假设。SM22α-HIF-1α - / -小鼠在正常缺氧和急性或慢性缺氧条件下表现出明显高于野生型（WT）的右心室收缩压（RVSP），而没有组织学证据表明血管重构加剧。此外，在正常缺氧和急性缺氧后，SM22α-HIF-1α - / -小鼠分离的PASMC中肌球蛋白轻链（MLC）磷酸化（SMC张力的决定因素）比WT PASMC更高。此外，HIF-1α的过表达降低了HIF-1α-无效SMC的MLC磷酸化。在常氧和缺氧情况下，PASMC HIF-1α通过降低MLC磷酸化维持低肺血管张力。PASMC HIF-1α表达受损可能导致肺动脉高压特征的血管收缩加剧。
Hypoxia inducible factor-1α HIF-1α an oxygen (O2)-sensitive transcription factor, mediates transcriptional responses to low O2 tension states. While acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia can cause vascular remodeling and pulmonary hypertension, conflicting data exists surrounding the role of HIF-1α in modulating pulmonary vascular tone. To investigate the role of smooth muscle cell (SMC) specific HIF-1α in regulating pulmonary vascular tone. Mice with a SMC specific deletion of HIF-1α (SM22α-HIF-1α−/−) were created to test the hypothesis that pulmonary artery smooth muscle cell (PASMC) HIF-1α modulates pulmonary vascular tone and the response to hypoxia. SM22α-HIF-1α−/− mice exhibited significantly higher right ventricular systolic pressure (RVSP) compared to wild-type (WT) littermates under normoxia and with exposure to either acute or chronic hypoxia in the absence of histologic evidence of accentuated vascular remodeling. Moreover, myosin light chain (MLC) phosphorylation, a determinant of SMC tone, was higher in PASMC isolated from SM22α-HIF-1α−/− mice compared to WT PASMC, during both normoxia and after acute hypoxia. Further, over-expression of HIF-1α decreased MLC phosphorylation in HIF-1α-null SMC. In both normoxia and hypoxia, PASMC HIF-1α maintains low pulmonary vascular tone by decreasing MLC phosphorylation. Compromised PASMC HIF-1α expression may contribute to the heightened vasoconstriction that characterizes pulmonary hypertension.