Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells
Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells
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DOI：
10.1161/circulationaha.107.716241
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发表时间：
2008-04-22
期刊：
影响因子：
37.8
通讯作者：
Perrella, Mark A.
中科院分区：
文献类型：
--
作者：
Fredenburgh, Laura E.;Liang, Olin D.;Perrella, Mark A.
背景-环氧化酶-2（考克斯-2）在缺氧时肺动脉平滑肌细胞（PASMCs）中表达上调，可能在肺对缺氧的反应中起保护作用。选择性的考克斯-2抑制可能具有有害的肺血管的后果在hypoxia.Methods和Results-To调查的作用考克斯-2在肺血管反应缺氧，我们进行了野生型和考克斯-2缺陷小鼠慢性常压缺氧模型。考克斯-2基因敲除小鼠在缺氧后发生严重的肺动脉高压，右心室收缩压过度升高，右心室显著肥大，血管重塑显著。考克斯-2缺陷小鼠的肺血管重构的特征是PASMC肥大，但不增加增殖。此外，考克斯-2缺陷小鼠缺氧后肺中内皮素-1受体（ETA）显著上调。同样，选择性药理学抑制野生型小鼠的考克斯-2可加重缺氧诱导的肺动脉高压，导致PASMC肥大和肺小动脉ETA受体表达增加。体外缺氧过程中血管平滑肌细胞中考克斯-2的缺失增强了牵引力并增强了细胞外基质的收缩性。治疗考克斯-2缺陷PASMCs与伊洛前列素，前列腺素I-2类似物，前列腺素E-2废除了有效的收缩反应，缺氧和恢复野生型phenotype. Conclusions，我们的研究结果表明，缺氧诱导的肺动脉高压和血管重塑加剧的情况下，考克斯-2增强ETA受体表达和增加PASMC肥大。考克斯-2缺陷型PASMC对缺氧具有适应不良的反应，表现为过度的收缩性，这可以通过考克斯-2衍生的前列腺素I-2或前列腺素E-2来挽救。
Background-Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia.Methods and Results-To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ETA) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ETA receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I-2 analog, and prostaglandin E-2 abrogated the potent contractile response to hypoxia and restored the wild-type phenotype.Conclusions-Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ETA receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I-2 or prostaglandin E-2.