5-HT2aR contributes to pulmonary arterial hypertension by modulating the AHR pathway.

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by pathological remodeling of the pulmonary vasculature. The serotonin 2A receptor (5-HT2aR, encoded by Htr2a), a G protein-coupled receptor expressed in the pulmonary vascular wall, has been implicated in the pathogenesis of PAH. However, the effect of 5-HT2aR deficiency has not been investigated in rat models relevant to human disease and the underlying mechanisms remain unclear. In this study, we generated Htr2a knockout rats using the CRISPR/Cas9 system and established PAH models using monocrotaline (MCT, 60 mg/kg) or a combination of SU5416 (20 mg/kg) and hypoxia (10 % O2). The results of model evaluations indicated that Htr2a deficiency significantly attenuated PAH phenotypes in both MCT- and SU/Hx-induced models, including reduced right ventricular systolic pressure, reduced right ventricular hypertrophy, and decreased medial wall thickness and muscularization of distal pulmonary arterioles. RNA sequencing of lung tissue revealed that Htr2a knockout reversed disease-associated gene expression changes, notably downregulating Cyp1a1, Cyp1b1, and Ahrr, which are key targets of the aryl hydrocarbon receptor (AHR) signaling pathway. These results were confirmed by qPCR. Collectively, our findings demonstrate that loss of 5-HT2aR mitigates experimental PAH, potentially via suppression of AHR pathway-related gene expression. These findings provide mechanistic insight into 5-HT2aR function and suggest its potential as a therapeutic target in PAH.