Transection of the cervical sympathetic trunk ameliorates pulmonary arterial hypertension by reprogramming transcription factor networks and alternative splicing in rat model

Background Pulmonary arterial hypertension (PAH) is mostly induced by excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) with undefined mechanism. This study investigated the function and mechanism of transection of the cervical sympathetic trunk (TCST) on the progression of monocrotaline (MCT)-induced PAH in rats and explored the underlying mechanism. Methods A rat model of PAH was established by MCT injection. We evaluated the restoration of pulmonary architecture and hemodynamic parameters following TCST. Transcriptome sequencing (RNA-seq) was performed to identify key regulatory genes and signaling pathways that are particularly correlated with PASMC proliferation. The identified genes and pathways were further validated in the PAH model. Results TCST significantly attenuated pulmonary vascular remodeling and improved hemodynamic condition, as evidenced by reduced mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP), and right ventricular hypertrophy index (RVHI) compared to the PAH+sham group. RNA-seq analysis revealed that TCST suppressed calcium signaling and cell proliferation pathways, with downregulated DEGs enriched in immune responses, inflammatory responses, and the calcium signaling pathway. Differential expression analysis showed downregulation of the calcium pathway genes Adra1d and Tacr1 , as well as their transcriptional regulator Foxa3 . Further qPCR experiments confirmed decreased levels of Adra1d, Tacr1, Plcb1 , and Foxa3 . ELISA confirmed the inhibited expression of inositol trisphosphate (IP3), which directly regulate intracellular calcium concentration. Conclusions We explored the mechanism of TCST in ameliorating PAH by the suppression of the Foxa3/Adra1d-Tacr1 axis involved in calcium signaling, revealing a novel link between PAH and calcium-driven vascular remodeling, and a mechanistic basis for TCST as a potential therapeutic strategy for PAH.