Cellular Signalling Networks in High Altitude Pulmonary Hypertension: From Canonical Pathways to Emerging Targets.

High altitude pulmonary hypertension (HAPH) is a complex disease featured by hypoxia-induced pulmonary vasoconstriction and remodelling of small pulmonary arterioles, which could lead to increased pulmonary pressures and right ventricular hypertrophy and eventually result in heart failure. The temporal trajectory of HAPH progression can be divided into three overlapping phases: hypoxic pulmonary arterioles vasoconstriction, hypoxic pulmonary arterioles remodelling and even right heart failure. Each phase is governed by distinct molecular engines and cellular effectors that translate hypoxia physiological adaption into irreversible cardiopulmonary dysfunction. This review describes the intricate cellular signalling networks involved in the pathogenesis of HAPH, integrating canonical pathways such as HIF, MAPK and BMP with emerging targets like Wnt/β-catenin, Notch, Hippo-YAP and IL-6. Inhibiting the HIF signalling pathway, modulating the MAPK pathway and suppressing the BMP, Wnt/β-catenin, Notch, Hippo-YAP and IL-6 pathways have shown potential in reducing vascular remodelling and right ventricular dysfunction. Despite encouraging progress, the clinical translation remains constrained by a lack of deeper understanding of the signalling networks in HAPH. A comprehensive understanding of these signalling pathways in HAPH may yield critical insights into the disease's pathogenesis and facilitate the development of targeted intervention strategies. Future research should focus on elucidating the molecular mechanisms underlying these pathways, exploring genetic and environmental interactions, validating intervention targets, developing biomarkers, utilising systems biology approaches and conducting clinical trials.