Introduction
Under physiological conditions, the adult pulmonary circulation is maintained as a high-flow, low-pressure and low-resistant system through which the entire cardiac output (CO) must pass. Exposure to hypoxia leads to the constriction of small resistant arteries in the lung, referred to as hypoxic pulmonary vasoconstriction (HPV) (Euler USV, 1946). It is a physiological mechanism to divert blood to better oxygenated lung segments and optimize gas exchange by adapting blood flow (perfusion) to alveolar ventilation. This is beneficial ifregional obstruction of airflow occurs and between 30-70% of the lung is exposed to hypoxia (Sylvester, Shimoda, Aaronson & Ward, 2012); if the vasoconstricted area is less than 30%, the effect of lower PO2 is negligible. In the case of global alveolar hypoxia, such as occurs at high altitude, HPV can be detrimental because it leads to a sustained overall vasoconstriction and a significant increase in pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) – see Box 1 (Dunham-Snary et al., 2017; Penaloza & Arias-Stella, 2007b; Young, Williams & Thompson, 2019).
Sustained exposure to hypoxia leads to structural changes in pulmonary vessels that increase vascular stiffness and resistance to blood flow. HPV and vascular remodelling, together with a rise in haematocrit and thus blood viscosity, comprise the components of hypoxia-induced pulmonary hypertension (HPAH), which places an increased workload on the right ventricle (Dunham-Snary et al., 2017; Julian & Moore, 2019; Penaloza & Arias-Stella, 2007a; Soria, Egger, Scherrer, Bender & Rimoldi, 2016; Wilkins, Ghofrani, Weissmann, Aldashev & Zhao, 2015; Young, Williams & Thompson, 2019). Heterogeneity in HPV in the pulmonary circulation is credited with an important role in hypoxia-induced pulmonary oedema (HAPE); differential HPV may lead to over perfusion of some regions of the lung, causing oedema. Excessive erythrocytosis leading to hyper-viscosity characterises chronic mountain sickness (CMS) and emphasises the importance of correcting measurements of pulmonary vascular resistance for haematocrit when diagnosing HAPH. Here we focus on HPAH and the contribution from studies in animals and humans exposed to chronic hypoxia to understanding underlying mechanisms and prioritising pharmacological targets.