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Translating Basic Research Into Clinical Practice |

Hypoxic pulmonary vasoconstriction: from molecular mechanisms to medicine

Kimberly J. Dunham-Snary, PhD; , MD, PhD; Edward A. Sykes, PhD; Amar Thakrar, MD; Leah RG. Parlow; Jeffrey D. Mewburn; Joel L. Parlow, MD; Stephen L. Archer, MD
Author and Funding Information

Funding Sources: This work is supported by the National Institutes of Health RO1-HL071115 and 1RC1HL099462, Canadian Institutes for Health Research (CIHR) Foundation Award 333058, the Canada Foundation for Innovation (CFI) 33518 and 229252, The WJ Henderson Foundation and a Canada Research Chair 229252. KDS and DW are funded by awards from the Canadian Vascular Network Scholar Award (CIHR).

Department of Medicine, Queen's University, Kingston, Ontario, Canada

Address for correspondence: Stephen L. Archer MD. FRCP(C), FAHA, FACC, Professor and Head, Department of Medicine, Queen's University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, Ontario, Canada, K7L 3N6.


Copyright 2016, . All Rights Reserved.


Chest. 2016. doi:10.1016/j.chest.2016.09.001
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Abstract

Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation-perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in PASMC. This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and HIF-1α, leading to adverse pulmonary vascular remodelling and pulmonary hypertension (PH). In the non-ventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis that optimizes systemic PO2 without altering pulmonary artery pressure. In single-lung anesthesia, HPV reduces blood flow to the non-ventilated lung thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PA pressure and initiates PH. Exaggerated or heterogeneous HPV contributes to high altitude pulmonary edema. Conversely, impaired HPV, whether due to diseases (COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudo-hypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen-sensing are important in human health and disease.


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