Pulmonary Arterial Hypertension Induces Sex-Specific Right Ventricular Transcriptomic Remodeling

Objective: Pulmonary arterial hypertension (PAH) imposes chronic pressure overload on the right ventricle (RV), leading to progressive remodeling and ultimately RV failure, the primary cause of mortality in the disease. Although PAH is more prevalent in women, men exhibit worse RV outcomes, underscoring the importance of sex-specific mechanisms governing RV adaptation and failure. Importantly, ventricular diastolic stiffening is a strong predictor of disease severity and poor prognosis, and prior hemodynamic and tissue-level studies indicate that RV remodeling transitions from compensatory hypertrophy to maladaptive stiffening as disease progresses. Here, we investigate whether sex-dependent RV transcriptomic remodeling reflects distinct trajectories toward ventricular stiffening and dysfunction. Methods: PH was induced in male and female Sprague-Dawley rats using the sugen-hypoxia (SuHx) model. Bulk RNA sequencing was performed on RV tissue after 4 and 8 weeks of SuHx, with confirmed hypertension and tightly distributed end-systolic and end-diastolic pressures. Equal-sized normotensive groups served as controls. Data were processed in Galaxy through differential expression analysis, with downstream processing and visualization performed using R and Gene Set Enrichment Analysis (GSEA). Results: RV transcriptomes clustered primarily by sex and treatment, without distinguishing SuHx timepoints, indicating early establishment of disease-specific transcriptional programs (Figure 1). SuHx induced enrichment of profibrotic, inflammatory, and apoptotic pathways, while suppressing key metabolic pathways (Figure 2). At baseline, male RVs exhibited higher enrichment of profibrotic and inflammatory pathways and reduced metabolic signaling compared with females, suggesting a predisposition toward stress-sensitive remodeling. After accounting for these baseline differences, female SuHx RVs showed greater enrichment of proliferation and angiogenic pathways (Figure 2). In contrast, male SuHx RVs reached greater absolute enrichment of profibrotic and apoptotic pathways, accompanied by pronounced suppression of mitochondrial metabolism. Notably, these transcriptional signatures correspond to higher end-systolic and end-diastolic pressures in male animals relative to stage-matched females, reflecting greater mechanical disease severity. Conclusions: These findings suggest that male RV exhibit a transcriptional profile characterized by heightened stress signaling, metabolic dysfunction, and cell death, which are features consistent with accelerated ventricular stiffening and progression toward failure. In contrast, female RVs engage transcriptional programs favoring extracellular matrix remodeling and cellular proliferation, indicating a more adaptive response to pressure overload. Together, these results link sex-dependent transcriptomic remodeling to organ-level hemodynamic severity and support ventricular stiffening, rather than hypertrophy alone, as a key determinant of maladaptive RV remodeling and outcomes in PAH. Funding: NSF CAREER 2046259, NHLBI 1R01HL155945, Conrad Prebys Foundation This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.