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Transection of the Cervical Sympathetic Trunk Ameliorates Pulmonary Arterial Hypertension probably by Suppressing Transcriptome Profile and calcium signaling in rat model

ABSTRACT: 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.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.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.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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE328273 | GEO | 2026/04/30

REPOSITORIES: GEO

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Project description:Abstract: Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV), decreased cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE) and ventricular-arterial decoupling). RNA sequencing revealed 2547 differentially regulated transcripts in MCT-RVF RVs. Multiple enriched gene ontology (GO) terms converged on mitochondria/metabolism, fibrosis, inflammation, and angiogenesis. The mitochondrial transcriptomic pathway is the most affected in RVF, with 413 dysregulated genes. Downregulated genes included tfam (−0.45-fold), suggesting impaired mitochondrial biogenesis, Cyp2e1 (−3.8-fold), a monooxygenase which when downregulated increases oxidative stress, dehydrogenase/reductase 7C (Dhrs7c) (−2.8-fold), consistent with excessive autonomic activation, and polypeptide N-acetyl-galactose-aminyl-transferase 13 (Galnt13), a known pulmonary hypertension (PH) biomarker (−2.7-fold). The most up-regulated gene encodes Periostin (Postn; 4.5-fold), a matricellular protein relevant to fibrosis. Other dysregulated genes relevant to fibrosis include latent-transforming growth factor beta-binding protein 2 (Ltbp2), thrombospondin4 (Thbs4). We also identified one dysregulated gene relevant to all disordered transcriptomic pathways, Annexin A1. This anti-inflammatory, phospholipid-binding mediator, is a putative target for therapy in RVF-PAH. Comparison of expression profiles in the MCT-RV with published microarray data from the RV of pulmonary artery-banded mice and humans with bone morphogenetic protein receptor type 2 (BMPR2)-mutations PAH reveals substantial conservation of gene dysregulation, which may facilitate clinical translation of preclinical therapeutic and biomarkers studies. Transcriptomics reveals the molecular fingerprint of RVF to be heavily characterized by mitochondrial dysfunction, fibrosis and inflammation.

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Transection of the Cervical Sympathetic Trunk Ameliorates Pulmonary Arterial Hypertension probably by Suppressing Transcriptome Profile and calcium signaling in rat model

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