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.