Grant: CIHR Fellowship

The body responds to changes in oxygen during development and adaptation to inadequate oxygen supply (hypoxia). Pulmonary hypertension (PH) affects thousands of Canadians. Like cancer, PH is marked by excess cell growth and impaired cell death, due in part to impaired oxygen sensing and metabolism. The majority of PH treatments target the vasospastic component of this disease. Understanding the mechanism of oxygen sensing and targeting impaired oxygen sensing in PH could provide new therapeutic targets. Nearly all blood vessels dilate in response to sudden-onset hypoxia, ensuring maximum blood flow and oxygen delivery to the organs. However, small pulmonary arteries (PA) in the lung constrict in response to even mild hypoxia, a process called hypoxic pulmonary vasoconstriction (HPV). HPV optimizes oxygen uptake by diverting blood flow to well-ventilated lung segments. HPV occurs through a rapid, reversible process that is intrinsic to the pulmonary artery smooth muscle cells (PASMC), and vasoconstriction is initiated by cellular changes that inhibit voltage-gated potassium channels and activate calcium channels. Elevation of cytosolic Ca2+ leads to vasoconstriction. It is thought that a sensor within the cell converts PO2 into a secondary messenger that regulates ion channels, enzymes and vascular tone. Prior research identified the mitochondrion (the powerhouse of the cell that generates energy) as the probable oxygen sensor in the PA and shown that changes in electron transport chain (ETC) function controls pulmonary vascular tone through alterations in cellular signalling. The goals of my research are to identify the molecular subunits of the mitochondrial ETC that respond to hypoxia and the differences between the mitochondria of PA and renal arteries, and investigate how these differences are linked to cell function. Identifying ETC subunits that mediate oxygen-sensing will provide novel therapeutic targets for PH and other diseases of impaired oxygen sensing.