Mitochondrial transplantation attenuates hypoxic pulmonary vasoconstriction

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.

Mitochondrial transplantation attenuates hypoxic pulmonary hypertension

“…The mechanism(s) involved in transplantation of exogenous mitochondria into smooth muscle cells of pulmonary arteries may be more complicated in vivo than in vitro as reported recently from other lab [16] and ours [8]. In addition to the direct interaction between mitochondrial membrane and cytoplasma membrane and the subsequent processes like fusion and or endocytosis as suggested from recent works of another lab [16] and ours [8], the other possible pathways may be related with the interspace and gap junctional channels between endothelial and smooth muscle cells as well as those between smooth muscle cells, since mitochondrial transfer between cells was reported in very recent studies [17, 18].…”

“…In experiments using Wilson's liver mitochondria or engineered ascorbate peroxidase (APEX)-labeling as mitochondrial tracer [8, 9, 10] we determined the borderlines of adjacent cells under lower amplification and then examined the area(s) under high amplification including the collagen fibrils in the intercellular space. Our ultrastructural examination unexpectedly identified the localization of individual mitochondria within the intercellular space between pulmonary artery endothelial cells and smooth muscle cells (Figure 2a), the “ongoing”-like and “accomplished”-like uptake of exogenous mitochondria into smooth muscle cells (Figure 2b).…”

“…To determine if exogenous mitochondria are functional in vivo as they were after transplantation into PASMCs in culture and into pulmonary arteries in vitro [8], we recovered mitochondria after their transplantation into pulmonary arteries in rats. Mitochondria were isolated from pulmonary arteries in rats after intravenous injection of the GFP-labeled then subjected to flow cytometry for sorting and recovery of the endogenous as well as GFP-labeled, exogenous mitochondria.…”

“…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].…”

“…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 therefore 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.…”