Mitochondrial transplantation attenuates hypoxic pulmonary vasoconstriction.

Juan Zhou,Qinghua Hu,Songling Huang,Jiwei Zhang,Xianqin Zeng,Jiansha Li,Tao Wang,Yankai Lu,Tongfei Li,Rui Xiao,Xiuyun Zhang,Liping Zhu

doi:10.18632/oncotarget.8893

Abstract

Hypoxia triggers pulmonary vasoconstriction, however induces relaxation of systemic arteries such as femoral arteries. Mitochondria are functionally and structurally heterogeneous between different cell types. The aim of this study was to reveal whether mitochondrial heterogeneity controls the distinct responses of pulmonary versus systemic artery smooth muscle cells to hypoxia. Intact mitochondria were transplanted into Sprague-Dawley rat pulmonary artery smooth muscle cells in culture and pulmonary arteries in vitro. Mitochondria retained functional after transplantation. The cross transplantation of mitochondria between pulmonary and femoral artery smooth muscle cells reversed acute hypoxia-induced alterations in cell membrane potential, [Ca2+]i signaling in smooth muscle cells and constriction or relaxation of arteries. Furthermore, the high or low amount of reactive oxygen species generation from mitochondria and their divergent (dis-)abilities in activating extracellular Ca2+-sensing receptor in smooth muscle cells were found to cause cell membrane potential depolarization, [Ca2+]i elevation and constriction of pulmonary arteries versus cell membrane potential hyperpolarization, [Ca2+]i decline and relaxation of femoral arteries in response to hypoxia, respectively. Our findings suggest that mitochondria necessarily determine the behaviors of vascular smooth muscle cells in response to hypoxia.

Highlights

Mitochondria are critical in the initiation of hypoxiainduced pulmonary vasoconstriction (HPV) [1, 2, 3, 4, 5]
We found that the transplantation of mitochondria derived from femoral artery smooth muscle cells (FASMCs) inhibited hypoxiainduced cell membrane potential depolarization and [Ca2+]i elevations in cultured pulmonary artery smooth muscle cells (PASMCs) preparations, attenuated hypoxia-induced constriction of isolated pulmonary arteries (PAs) in vitro, and vice versa
We identified the mechanisms underlying the effects of transplanted mitochondria, which was associated with the potent capability of generating reactive oxygen species (ROS) in PASMCs versus FASMCs in response to hypoxia

Summary

Introduction

Mitochondria are critical in the initiation of hypoxiainduced pulmonary vasoconstriction (HPV) [1, 2, 3, 4, 5]. Whether the difference between mitochondria represents the mechanism underlying distinct responses to hypoxia between pulmonary and systemic arteries is www.impactjournals.com/oncotarget undetermined according to Koch’s Postulates [2, 5, 8]. It warrants investigation employing a novel experimental strategy to illustrate the cause-effect relationship between mitochondria and the responses of SMCs to hypoxia. Mitochondria are active organelles [9, 10], whose function depends on their fusion, fission and/or division under (patho-)physiological circumstances such as hypoxia [10]. The replacement and/or mixture of different mitochondria can be expected to change their behaviors [9]

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