Daniela Valdez‐Jasso

Sex differences in cardiovascular physiology are often interpreted without accounting for growth-dependent scaling and cohort standardization. Here, we show that normalization strategy, estrogen status, and the timing of ovarian hormone loss interact critically to shape cardiac structure and passive myocardial mechanics in rats. Notably, early estrogen loss increases right ventricular stiffness independent of hemodynamic load, underscoring the importance of experimental design in interpreting sex-specific phenotypes.

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.

Pulmonary arterial hypertension (PAH) is marked by vascular remodeling, yet the role of adventitial fibrosis-and its modulation by sex and hormonal status-remains unclear. We examined stage-specific adventitial remodeling and pulmonary artery adventitial fibroblast (PAAF) mechanosensitivity in male, ovary-intact female, and ovariectomized (OVX) female Sprague-Dawley rats with SuHx-induced PAH. Hemodynamics, pulmonary artery histology, and adventitia-specific transcriptional profiling were integrated with in vitro assays of PAAFs exposed to defined substrate stiffness and stretch. All groups developed comparable increases in mean pulmonary arterial pressure, but vascular resistance shift and adventitial fibrosis diverged by sex: intact females showed attenuated increase in pulmonary vascular resistance and transient collagen accumulation, whereas OVX females mirrored the sustained, male-like progression. Extracellular matrix (ECM) gene activation occurred without smooth muscle actin induction, suggesting noncanonical fibrotic pathways. In vitro, intact female PAAFs required higher substrate stiffness to induce profibrotic gene expression, indicating a hormone-modulated stiffness threshold. OVX PAAFs showed persistent transcriptional reprogramming, while stretch-induced ECM upregulation occurred predominantly in male-derived PAAFs. These findings demonstrate that adventitial fibrosis in PAH is shaped by both hormonal and chromosomal sex, independent of hemodynamic severity, and highlight fibroblast mechanosensitivity as a potential target for stage- and sex-specific interventions.

Pulmonary arterial hypertension (PAH) induces chronic pressure overload on the right ventricle (RV), leading to progressive remodeling and eventual failure. While PAH is more prevalent in women overall, men and postmenopausal women have worse clinical outcomes. Here, we investigated how sex and ovarian hormones influence RV remodeling during the progression of PAH. Using the sugen-hypoxia (SuHx) rat model, we assessed RV hemodynamics, tissue mechanics, and collagen composition in male, ovary-intact female, and ovariectomized (OVX) female rats across four disease stages. While all three groups experienced elevated pulmonary and ventricular pressures and rapidly responded with hypertrophy and stiffening, RV remodeling progressed differently in the absence of ovarian hormones. Male and OVX rats exhibited marked increases in end-diastolic pressure and myocardial stiffness, as well as higher chamber elastances. Ovary-intact female rats largely preserved diastolic function with milder stiffening. Collagen accumulation was observed in all groups, but only male and OVX rats exhibited significant elevations in pyridinoline cross-linking-aligning with the most severe additional mechanical changes, namely increased passive stiffness. This suggests that ovarian hormones moderate the severity of SuHx-induced RV remodeling by limiting myocardial stiffening and collagen cross-linking. These findings emphasize the need to consider sex and hormonal status in preclinical PAH research and suggest that extracellular matrix cross-linking may be a targetable contributor to maladaptive right heart remodeling.

Pulmonary arterial hypertension (PAH) induces chronic pressure overload on the right ventricle (RV), driving remodeling, while the left ventricle (LV) remains largely preserved. The interventricular septum is often modeled as part of the LV; however, its role as a mechanically adaptive structure during PAH progression remains poorly understood. This study investigates full-thickness septal tissue mechanics in male and female rats. RV and LV hemodynamics, septal morphology, and planar biaxial septum mechanical properties were measured in normotensive controls and rats at Weeks 4, 8, and 12 of pulmonary hypertension using the sugen-hypoxia (SuHx) rat model of PAH. Biaxial stress-strain data were fit with an exponential Fung-type constitutive model for quantitative comparison across groups. RV hemodynamics varied by both sex and disease stage, while LV hemodynamics only showed sex differences (males had larger LV volumes). Despite similar RV end-systolic pressures, septal adaptation was sex-specific. Septal tissues exhibited nonlinear, nearly isotropic mechanical behavior. Starting from the same baseline stiffness, female septal tissues became significantly more compliant at Week 4, while male septal tissues remained unchanged. By Week 8, the females returned to baseline stiffness, while the males hit their peak compliance. By Week 12, male and female septa converged to similar stiffnesses. Septal mechanical properties adapt during RV pressure overload, becoming more compliant with advancing RV remodeling. The degree and timing of remodeling are sex- and disease stage-dependent. These distinct patterns suggest septal mechanics play a functional role in modulating RV-LV interaction and support the need to treat the septum as an independent structure contributing to both chambers.

Combining hemodynamic and morphological measurements from male, female, and ovariectomized female pulmonary arterial hypertension (PAH) rats revealed distinct adaptation mechanisms despite similar pressure overload. Males showed the most diastolic stiffening. Ovariectomized females had enhanced myocyte contractility and calcium transient upregulation. Ovary-intact females primarily responded with hypertrophy, experiencing milder passive myocardial stiffening and no changes in myocyte shortening. These findings suggest potential sex-specific pathways in right ventricular (RV) adaptation to PAH, with implications for targeted interventions.

Pulmonary arterial hypertension (PAH) presents a significant challenge to right ventricular (RV) function due to progressive pressure overload, necessitating adaptive remodeling in the form of increased wall thickness, enhanced myocardial contractility and stiffness to maintain cardiac performance. However, the impact of these remodeling mechanisms on RV mechanics in not clearly understood. In addition, there is a lack of quantitative understanding of how each mechanism individually influences RV mechanics. Utilizing experimental data from a rat model of PAH at three distinct time points, we developed biventricular finite element models to investigate how RV stress and strain evolved with PAH progression. The finite element models were fitted to hemodynamic and morphological data to represent different disease stages and used to analyze the impact of RV remodeling as well as the altered RV pressure. Furthermore, we performed a number of theoretical simulation studies with different combinations of morphological and physiological remodeling, to assess and quantify their individual impact on overall RV load and function. Our findings revealed a substantial 4-fold increase in RV stiffness and a transient 2-fold rise in contractility, which returned to baseline by week 12. These changes in RV material properties in addition to the 2-fold increase in wall thickness significantly mitigated the increase in wall stress and strain caused by the progressive increase in RV afterload. Despite the PAH-induced cases showing increased wall stress and strain at end-diastole and end-systole compared to the control, our simulations suggest that without the observed remodeling mechanisms, the increase in stress and strain would have been much more pronounced. Our model analysis also indicated that while changes in the RV's material properties-particularly increased RV stiffness - have a notable effect on its mechanics, the primary compensatory factor limiting the stress and strain increase in the early stages of PAH was the significant increase in wall thickness. These findings underscore the importance of RV remodeling in managing the mechanical burden on the right ventricle due to pressure overload.

For the last couple of decades, a growing trend in computational cardiovascular research has been to 50 move away from generalized and simplistic models to personalized and patient-specific models. In spite of 51 substantial research effort and a continuous push for models representing precision medicine, however, 52 seemingly obvious differences such as those between male and female hearts remain understudied and 53 often neglected. The paper from St. Pierre et al presents a systematic review of the anatomy, function, 54 and physiological adaptation found in male and female hearts. The study reveals a range of significant 55 differences, and argue for increased research and design of sex-specific diagnostic criteria for earlier and 56 more precise diagnosis of cardiac disease in women. provide support for previous experimental results on the impact of pericardiectomy on cardiac function.The final contribution in this special issue, from Odeigah et al is also focused on pulmonary hypertension