Mechanistically, an accumulating body of evidence suggests that mitochondrial function is rate-limiting for sensing as well as initiating the paSMC contraction by producing reactive oxygen species (ROS) in response to decreasing oxygen levels. At high altitudes and under pathophysiological conditions causing alveolar hypoxia (e.g., chronic obstructive pulmonary disease (COPD) or low respiratory drive) paSMCs may be chronically forced to increase their tone. Specifically, paSMCs can sense oxygen partial pressure and increase their tone when exposed to hypoxia-a special feature of paSMCs located in small pulmonary arteries known as hypoxic pulmonary vasoconstriction (HPV). In the lung, SMCs of pulmonary arteries (paSMCs) constrict or relax depending on the oxygen level to optimize gas exchange by matching alveolar perfusion to local ventilation. Our findings suggest a critical role for NFAT5 as a suppressor of OXPHOS-associated gene expression, mitochondrial respiration, and ROS production in pulmonary artery SMCs that is vital to limit ROS-dependent arterial resistance in a hypoxic environment.Īdequate adjustment of the vascular SMC tone to different environmental conditions is vital for the function of any organ as it controls the resistance of arteries and arterioles by regulating their diameter and consequently the local blood supply. Scavenging of mitochondrial ROS normalized the raise in RVSP. Right ventricular functions were impaired while pulmonary right ventricular systolic pressure (RVSP) was amplified in hypoxia-exposed Nfat5 (SMC)−/− versus Nfat5 fl/fl mice. In vitro, hypoxia-exposed Nfat5-deficient pulmonary artery SMCs elevated the level of OXPHOS-related transcripts, mitochondrial respiration, and production of reactive oxygen species (ROS). Exposure to hypoxia promoted the expression of genes associated with metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in Nfat5 (SMC)−/− versus Nfat5 fl/fl lungs. Regulatory functions of NFAT5 were investigated in cultured artery SMCs and lungs from control ( Nfat5 fl/fl) and SMC-specific Nfat5-deficient ( Nfat5 (SMC)−/−) mice. Here, we explored the functional role of the transcription factor nuclear factor of activated T-cells 5 (NFAT5/TonEBP) in the hypoxic lung. While these responses require adjustment of the vascular SMC transcriptome, regulatory elements are not well defined in this context. Chronic hypoxia increases the resistance of pulmonary arteries by stimulating their contraction and augmenting their coverage by smooth muscle cells (SMCs).
0 Comments
Leave a Reply. |