Reactive oxygen species induced Ca2+ influx via TRPV4 and microvascular endothelial dysfunction in the SU5416/hypoxia model of pulmonary arterial hypertension

被引：71

作者：

Suresh, Karthik ^{[1
]}

Servinsky, Laura ^{[1
]}

Jiang, Haiyang ^{[1
]}

Bigham, Zahna ^{[1
]}

Yun, Xin ^{[1
]}

Kliment, Corrine ^{[1
]}

Huetsch, John ^{[1
]}

Damarla, Mahendra ^{[1
]}

Shimoda, Larissa A. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD 21205 USA

来源：

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY | 2018年 / 314卷 / 05期

关键词：

TO-MESENCHYMAL TRANSITION; INDUCED CALCIUM INFLUX; INDUCIBLE FACTOR-I; NITRIC-OXIDE; MITOCHONDRIAL MORPHOLOGY; OXIDATIVE STRESS; NADPH OXIDASE; CELLS; PHOSPHORYLATION; METABOLISM;

D O I：

10.1152/ajplung.00430.2017

中图分类号：

Q4 [生理学];

学科分类号：

071003 ;

摘要：

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by elevations in pulmonary arterial pressure, in part due to formation of occlusive lesions in the distal arterioles of the lung. These complex lesions may comprise multiple cell types, including endothelial cells (ECs). To better understand the molecular mechanisms underlying EC dysfunction in PAH, lung microvascular endothelial cells (MVECs) were isolated from normoxic rats (N-MVECs) and rats subjected to SU5416 plus hypoxia (SuHx), an experimental model of PAH. Compared with N-MVECs, MVECs isolated from SuHx rats (SuHx-MVECs) appeared larger and more spindle shaped morphologically and expressed canonical smooth muscle cell markers smooth muscle-specific alpha-actin and myosin heavy chain in addition to endothelial markers such as Griffonia simplicifolia and von Willebrand factor. SuHx-MVEC mitochondria were dysfunctional, as evidenced by increased fragmentation/fission, decreased oxidative phosphorylation, and increased reactive oxygen species (ROS) production. Functionally, SuHx-MVECs exhibited increased basal levels of intracellular calcium concentration ([Ca2+](i)) and enhanced migratory and proliferative capacity. Treatment with global (TEMPOL) or mitochondria- specific (MitoQ) antioxidants decreased ROS levels and basal [Ca-2](i) in SuHx-MVECs. TEMPOL and MitoQ also decreased migration and proliferation in SuHx-MVECs. Additionally, inhibition of ROS-induced Ca2+ entry via pharmacologic blockade of transient receptor potential vanilloid-4 (TRPV4) attenuated [Ca-2](i), migration, and proliferation. These findings suggest a role for mitochondrial ROS-induced Ca2+ influx via TRPV4 in promoting abnormal migration and proliferation in MVECs in this PAH model.

引用

页码：L893 / L907

页数：15

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