The Critical Role of Dynamin-Related Protein 1 in Hypoxia-Induced Pulmonary Vascular Angiogenesis.
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by pulmonary vascular obstruction due in part to excessive pulmonary artery endothelial cells (PAECs) migration and proliferation. The mitochondrial fission protein dynamin-related protein-1 (DRP1) has important influence on pulmonary vascular remodeling. However, whether DRP1 participates in the development and progression of pulmonary vascular angiogenesis has not been reported previously. To test the hypothesis that DRP1 promotes the angiogenesis via promoting the proliferation, stimulating migration, and inhibiting the apoptosis of PAECs in mitochondrial Ca(2+)-dependent manner, we performed following studies. Using hemodynamic analysis and morphometric assay, we found that DRP1 mediated the elevation of right ventricular systemic pressure (RVSP), right heart hypertrophy, and increase of pulmonary microvessels induced by hypoxia. DRP1 inhibition reversed tube network formation in vitro stimulated by hypoxia. The mitochondrial Ca(2+) inhibited by hypoxia was recovered by DRP1 silencing. Moreover, pulmonary vascular angiogenesis promoted by DRP1 was reversed by the specific mitochondrial Ca(2+) uniporter inhibitor Ru360. In addition, DRP1 promoted the proliferation and migration of PAECs in mitochondrial Ca(2+)-dependent manner. Besides, DRP1 decreased mitochondrial membrane potential, reduced the DNA fragmentation, and inhibited the caspase-3 activation, which were all aggravated by Ru360. Therefore, these results indicate that the mitochondrial fission machinery promotes migration, facilitates proliferation, and prevents from apoptosis via mitochondrial Ca(2+)-dependent pathway in endothelial cells leading to pulmonary angiogenesis.
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.
Tingting
T
Shen
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.
Na
N
Wang
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.
Xiufeng
X
Yu
Jiucheng
J
Shi
Qian
Q
Li
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.
Chen
C
Zhang
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.
Li
L
Fu
Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, China.
Shuang
S
Wang
Department of Pharmacology, College of Basic Medicine, Harbin Medical University, Daqing, China.
Yan
Y
Xing
Department of Pathophysiology, College of Basic Medicine, Harbin Medical University, Daqing, China.
Xiaodong
X
Zheng
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.
Lei
L
Yu
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing, China.|Biopharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, China.
Daling
D
Zhu
D000818:Animals; D001158:Arteries / Q000166:cytology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D034281:Dynamins / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism
C486391:Dnm1l protein, mouse; D034281:Dynamins; D002118:Calcium
ANGIOGENESIS; HYPOXIA; MITOCHONDRIAL CALCIUM; MITOCHONDRIAL FISSION