To decipher the hypoxic pulmonary hypertension: Vascular heterogeneity and the hypothesis of hypoxic responsive threshold

Pulmonary hypertension (PH) is a complex and multi-factorial chronic disease characterized by progressively increased pulmonary vascular resistance and vascular remodeling, and it has been recognized as ‘the cancer of cardiovascular diseases’ because of its high morbidity and mortality. Pathophysiological changes of pulmonary arteries, which implicate endothelial dysfunction, smooth muscle cell proliferation, and increased vasoconstriction, decrease the lumen area of the pulmonary microvasculature, optimizing the pulmonary ventilation/perfusion ratio as well as causing fixed elevation of pulmonary resistance. Among various types of PH, hypoxic pulmonary hypertension (HPH) which occurs in patients with cardiopulmonary disease or in residents at high altitude has aroused great interest in researchers. Intriguingly, synchronously exposed to the hypoxic circumstances, the peripheral vessels make responses different from pulmonary arteries, which, besides the effects exerted by nervus and the microenvironment (involving the inflammatory mediators, angiotensin II and other ingredients), has always been expounded as the vascular heterogeneity. Nevertheless, nobody has articulated such heterogeneity and its mechanism to date. Based on our prior experiments, we propound the hypothesis of hypoxic responsive threshold (HRT) for the first time, which means that once the partial pressure of oxygen diminishes to certain degree, vessel in different tissues reacts via the reactive oxygen species (ROS)–potassium channels (K_v)–hypoxia inducible factors (HIF) triangle, resulting in hypoxic vasoconstriction and vascular remodeling. HRT, varying according to different parts of the body, has close relationship with normoxic condition of the vessels. Physiological oxygen-rich milieu determines higher pulmonary vascular HRT, which explains why the pulmonary arterioles are more susceptible to hypoxia.