Pulmonary hypertension develops in patients with alveolar hypoxia arising from chronic lung diseases or high altitude exposure. These diseases affect large numbers of patients, and hypoxia-induced pulmonary vascular remodeling is the most common cause of pulmonary hypertension (PH). We propose that remodeling is triggered by mitochondrial O2 sensors that initiate redox signaling in vascular smooth muscle, thereby promoting cell contraction, growth and proliferation. Our previous work implicates mitochondria as a source of reactive oxygen species (ROS) signals that activate functional responses to acute hypoxia in pulmonary artery smooth muscle cells (PASMC). We now propose to test whether these signals also drive vascular remodeling and metabolic reprogramming in PASMC, leading to PH during chronic hypoxia. The role of ROS in PH has been highly controversial, so these studies are critically important for clarifying this issue. Chronic hypoxia activates redox signaling and induces Hypoxia-Inducible Factors (HIF-1 and HIF-2) in pulmonary vascular cells. This promotes metabolic reprogramming toward glycolysis and away from mitochondrial oxidative phosphorylation. We will test whether this reprogramming promotes vascular remodeling and PH. Hypoxia and ROS also activate AMP-dependent Protein Kinase (AMPK), a cellular energy sensor that activates catabolic pathways and inhibits anabolic metabolism, potentially opposing the remodeling response. We will determine whether AMPK activation can limit the growth, proliferation and metabolic reprogramming of PASMC, thereby opposing the development of PH. To achieve these aims we have assembled a powerful set of tools to quantify and modify redox signaling and metabolic pathways, which will be applied in genetic mouse models of PH and in pulmonary vascular cells from patients with pulmonary hypertension. These studies will provide novel insight into the mechanisms regulating the remodeling and PH arising in response to chronic hypoxia, and will identify potential therapeutic targets for the treatment of hypoxia-associated PH in humans.
|Effective start/end date||1/1/14 → 12/31/18|
- National Heart, Lung, and Blood Institute (5R01HL122062-04)