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

• A new hypotheses for the hypoxic pulmonary hypertension is proposed.
• We propound the hypothesis of hypoxic responsive threshold (HRT) for the first time to explain vascular heterogeneity.
• The reactive oxygen species (ROS)-potassium channels (Kv)–hypoxia inducible factors (HIF) triangle plays an important role in hypoxic vasoconstriction and vascular remodeling.

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 (Kv)–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.

Based on our hypotheses, the interaction of the oxygenic atmosphere and arterioles can be summarized into syllogism, namely physiological normoxic accommodation stage (I), pathological hypoxic responsive stage (II), and ultimate super-hypoxic exhaustion stage (III). All the three phases implicate the reactive oxygen species (ROS)–potassium channels (Kv)–hypoxia inducible factors (HIF) triangle. In the middle this figure shows the relationship among ROS, Kv and HIF: ① ROS directly suppress the activity of K+ channels, while decreased Kv currents result in membrane depolarization, promoting Ca2+ influx through voltage-dependent Ca2+ channels (VDCC) opening, inducing vascular constriction; ② The increased ROS could activate and stabilize HIF-1α, and HIF-1α could also increase ROS production; ③ Active HIF-1α may downregulate Kv 1.5 expression through its downstream signaling. Left displays the vascular modeling in stage I, contributing to the higher hypoxic responsive threshold of pulmonary arterioles. Right exhibits the pathogenesis of HPH based on the ROS–Kv–HIF triangle. Figure optionsDownload as PowerPoint slide