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

Background Transection of the cervical sympathetic trunk (TCST) ameliorates pulmonary arterial hypertension (PAH), but the molecular mechanisms remain unclear. This study aimed to elucidate these mechanisms in monocrotaline (MCT)-induced PAH rats through transcriptomic profiling. Methods PAH rats were divided into control, PAH, PAH + sham, and PAH + TCST groups. Therapeutic effects were evaluated by hemodynamics and histology. RNA-seq was performed on lung tissues to identify differentially expressed genes (DEGs), followed by transcription factor (TF) network analysis and alternative splicing analysis, with validation by qPCR and ELISA. Results TCST significantly reduced mPAP, RVSP, and RVHI, and attenuated vascular remodeling. RNA-seq identified 500 DEGs (61 upregulated, 439 downregulated). TF network analysis revealed that target genes of differentially expressed TFs were enriched in inflammation, proliferation, and calcium signaling. Multiple PAH-associated genes ( Bmp2 , Ptgs2 , Cxcl13, Wnt7b , Tacr1 , Adra1d ) were downregulated following TCST. Alternative splicing analysis showed that TCST modulated RNA-binding protein (RBP) expression and altered splicing patterns of PAH-relevant genes ( Aldh2 , Il1rn , Foxm1 ). qPCR and ELISA confirmed suppression of the Foxa3 / Adra1d - Tacr1 axis and reduced IP3 production. Conclusions TCST exerts therapeutic effects through selective reprogramming of TF networks and regulation of RBP-mediated alternative splicing, coordinately suppressing PAH-associated pathways at transcriptional and post-transcriptional levels. These findings provide mechanistic insights and a theoretical basis for developing neuromodulatory strategies for PAH.