The pulmonary vasculature constricts in response to acute alveolar hypoxia to redirect blood from poorly to better ventilated areas of the lung, which is an essential self-regulatory physiological response of the pulmonary vessels termed hypoxic pulmonary vasoconstriction (HPV). In contrast, different triggers of pulmonary hypertension (PH), including chronic hypoxia, lead to pathological reactions of the pulmonary vasculature, resulting in pulmonary vasculature remodeling that is characterized by excessive proliferation and attenuated apoptosis of vascular cells concomitant with reduction in the vascular lumen area. Despite intensive research in the last decades, the underlying mechanisms of HPV and vascular proliferation in PH have not yet been fully elucidated. It has been suggested that mitochondria play a key role in HPV, as well as in hypoxia and non-hypoxia dependent pathways that underlie pulmonary vascular remodeling. In both processes the mitochondrial membrane potential (MMP), which is an important characteristic of mitochondrial function and the main factor regulating the release of mitochondrial reactive oxygen species (ROS), could play a crucial role. It was hypothesized that knockout of the mitochondrial uncoupling protein 2 (UCP2) results in an increase of MMP and ROS emission that can regulate HPV and vascular remodeling in PH.Acute hypoxia induced an increase of MMP and ROS emission (O2 -, as well as H2O2) in pulmonary artery smooth muscle cells (PASMC) isolated from small precapillary arteries of rats and mice. MMP was also increased in precapillary PASMC isolated from experimental models of PH (chronic hypoxia-induced PH and monocrotaline [MCT]-induced PH) and from patients with idiopathic pulmonary arterial hypertension (IPAH) compared to respective controls. The increase of MMP in PH could have been the result of the utilization of increased glycolytically produced ATP, while concomitantly mitochondrial respiration was decreased in precapillary PASMC. Additionally, mitochondrial hyperpolarization could have also been mediated by UCP2 downregulation. UCP2 deficiency (UCP2-/-) caused an increase of MMP and ROS in small precapillary PASMC during normoxic baseline conditions and potentiated the increase of MMP and ROS in acute hypoxia. In parallel, UCP2 deficiency potentiated HPV and showed an increase of right ventricular systolic pressure (RVSP), right ventricle (RV) hypertrophy and vascular remodeling, thus mimicking PH in normoxic baseline conditions. The latter effect can at least partially be attributed to enhanced precapillary PASMC proliferation in UCP2 deficient mice that could be completely reversed by the application of the mitochondrial uncoupler, FCCP and partially by the treatment with ROS scavengers. These findings indicate a crucial role for mitochondrial hyperpolarization and increase of mitochondrial ROS emission in the development of PH. UCP2-/- mice exposed to 4 weeks of hypoxia did not display any differences in MMP compared to wild type (WT) controls. This finding can be explained by downregulation of UCP2 during chronic hypoxia as possible mechanisms to increase MMP in WT mice, which could not be activated in UCP2-/- mice during chronic hypoxia.The data of the current study thus suggest that an increase of MMP and ROS release could regulate HPV and vascular remodeling in PH. The mechanism for mitochondrial hyperpolarization in PH may be metabolic alterations and downregulation of UCP2 and was regulated by ROS. UCP2-/- deficiency lead to the development of the PH phenotype in mice via increase of MMP and partially via enhance of ROS emission in precapillary PASMC.
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