Pulmonary Pharmacology & Therapeutics · Oct 23, 2026
Cellular Senescence and Vascular Ageing in Pulmonary Hypertension: Molecular Mechanisms, Therapeutic Strategies, and Translational Endpoints
By Chen Y, Wang X, Gao M et al.
Increased right ventricular afterload, persistent pulmonary vascular remodelling, and the development of right heart failure are the hallmarks of pulmonary hypertension (PH). In PAH, therapies targeting the prostacyclin, nitric oxide-cyclic guanosine monophosphate, and endothelin pathways improve clinical status and haemodynamics, although established vascular remodelling frequently remains incompletely reversible. This review summarises data suggesting that the residual remodelling load in PH is influenced by vascular ageing, specifically stress-induced premature senescence-like phenotypes in pulmonary vascular wall cells. Endothelial repair failure, pulmonary artery smooth muscle cell secretory amplification, extracellular matrix (ECM) stiffening, senescence-associated secretory phenotype signalling, and mechano-metabolic reprogramming are examined as interconnected processes that attenuate vascular plasticity and consolidate disease progression. Pharmacological strategies discussed include senolytic and senomorphic approaches, activin/TGF-β superfamily modulation exemplified by sotatercept, matrix- and mechanotransduction-directed interventions, and metabolic modulation. Finally, vascular ageing-informed PH studies are proposed to incorporate concordant endpoints that align molecular target engagement with pulmonary vascular mechanics, right ventricular-pulmonary arterial (RV-PA) coupling, right ventricular function, and safety outcomes.