Abstract
Mitochondria are essential for the onset of hypoxia-induced pulmonary vasoconstriction and pulmonary vascular-remodeling, two major aspects underlying the development of pulmonary hypertension, an incurable disease. However, hypoxia induces relaxation of systemic arteries such as femoral arteries and mitochondrial heterogeneity controls the distinct responses of pulmonary versus femoral artery smooth muscle cells to hypoxia in vitro. The aim of this study was to determine whether mitochondrial heterogeneity can be experimentally exploited in vivo for a potential treatment against pulmonary hypertension. The intact mitochondria were transplanted into Sprague-Dawley rat pulmonary artery smooth muscle cells in vivo via intravenous administration. The immune-florescent staining and ultrastructural examinations on pulmonary arteries confirmed the intracellular distribution of exogenous mitochondria and revealed the possible mitochondrial transfer from pulmonary artery endothelial cells into smooth muscle cells in part through their intercellular space and intercellular junctions. The transplantation of mitochondria derived from femoral artery smooth muscle cells inhibited acute hypoxia-triggered pulmonary vasoconstriction, attenuated chronic hypoxia-induced pulmonary vascular remodeling, and thus prevented the development of pulmonary hypertension or cured the established pulmonary hypertension in rats exposed to chronic hypoxia. Our findings suggest that mitochondrial transplantation possesses potential implications for exploring a novel therapeutic and preventive strategy against pulmonary hypertension.
Highlights
Pulmonary hypertension is a lethal complication of patients with chronic lung diseases who usually experience hypoxemia
We performed the current study to explore whether mitochondria can be transplanted into pulmonary arteries in vivo, and if so whether the transplantation of mitochondria prepared from femoral artery smooth muscle cells (FASMCs) can be experimentally exploited to treat hypoxia-induced pulmonary hypertension (HPH) and whether the effectiveness of mitochondrial transplantation is mechanistically associated with their modulation of hypoxia–induced pulmonary vasoconstriction (HPV) and HPR
We found that the transplantation of mitochondria derived from FASMCs inhibited acute hypoxia-induced pulmonary vasoconstriction, restrained pulmonary vascular remodeling and pulmonary hypertension in rats exposed to chronic hypoxia
Summary
Pulmonary hypertension is a lethal complication of patients with chronic lung diseases who usually experience hypoxemia. Mitochondria in pulmonary artery smooth muscle cells (PASMCs) appear structurally and functionally distinct from those in systemic arteries [6, 7]. Our recent study employing cross transplantation of mitochondria between PASMCs and femoral artery smooth muscle cells (FASMCs) revealed that mitochondrial heterogeneity critically controls the distinct responses of pulmonary versus femoral artery under hypoxia [8]. We found that the transplantation of mitochondria derived from FASMCs inhibited hypoxia-induced cell membrane potential depolarization, [Ca2+]i elevations in PASMCs and attenuated hypoxia-triggered constriction of pulmonary arteries in vitro [8]. We performed the current study to explore whether mitochondria can be transplanted into pulmonary arteries in vivo, and if so whether the transplantation of mitochondria prepared from FASMCs can be experimentally exploited to treat HPH and whether the effectiveness of mitochondrial transplantation is mechanistically associated with their modulation of HPV and HPR
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