The Critical Role of Dynamin‐Related Protein 1 in Hypoxia‐Induced Pulmonary Vascular Angiogenesis

Abstract

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.

Mitochondria in endothelial cells: Sensors and integrators of environmental cues

“…Fission, on the other hand, is a key factor in vascular sprouting. In pulmonary ECs, DRP-1 activation, which induces mitochondrial fission, stimulates angiogenesis by promoting proliferation, migration, and inhibition of apoptosis in a mitochondrial Ca 2+ -dependent manner [19], [21]. A defective mitochondrial network is observed in several pathological settings, such as high glucose and ischemia-reperfusion, and also during EC aging, highlighting the importance of the fusion/fission cycle during disease development [22], [23], [24], [25].…”

The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics

“…Marsboom et al demonstrated that inhibition of HIF-1α or Drp1 reduces proliferation in pulmonary artery smooth muscle cells, suggesting that mitochondrial fragmentation can promote proliferation [147]. Furthermore, hypoxia induced fission may contribute to angiogenesis, as Drp1 was shown to mediate hypoxia-induced increases in pulmonary microvessels, and knockdown of Drp1 decreases CD31-positive blood vessels in a Ras-driven xenograft model [61,150]. In addition to these hypoxia-induced changes, HIF-1α has been shown to cooperate with other signaling nodes to promote pro-tumorigenic physiological changes.…”

Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation

“…While several studies have reported that ischemia reperfusion-induced mitochondrial fission is associated with decreased ROS production and apoptosis in neuronal cells and cardiomyocyte [ 15 16 21 ], little is known about the effect of mitochondrial dynamics on angiogenesis. As hypoxia is known to affect both angiogenesis and mitochondrial function, we examined that the effect of mitochondrial dynamics on angiogenesis [ 22 ]. In agreement with our results, Zhao et al confirmed that DRP1 plays critical roles in cell migration and invasion in breast cancer under hypoxic condition [ 23 ].…”