A 12-week high-fat diet in a murine model of pulmonary arterial hypertension induced sex-specific responses, with obese females showing a 30% increase in cardiomyocyte volume compared to obese males.
Does high-fat diet-induced obesity worsen lung vascular remodeling, hemodynamics, and cardiac function in a murine model of pulmonary arterial hypertension?
High-fat diet-induced obesity exacerbates pulmonary vascular remodeling and hemodynamics in a murine model of PAH, with distinct sex-specific profiles in right ventricular adaptation.
Abstract Background Comorbid obesity is prevalent in patients with pulmonary arterial hypertension (PAH) but its impact on pulmonary vascular disease remains controversial. We employed the EHITSN-KDITSN murine model of PAH, which closely recapitulates the human disease including the sex bias, to evaluate the impact of high-fat diet-induced obesity on lung vascular remodeling, lung hemodynamics, and cardiac function in this murine model. Methods Male and female EHITSN-KDITSN mice, 4 months of age, were subjected to an adjusted calories diet (60/fat) for 12-weeks. Hemodynamic measurements were performed using a Millar system. Lung and heart tissues were collected and subjected to histological analyses (Hematoxylin Eosin, wheat germ agglutinin (WGA) Alexa Fluor 494/DAPI staining) and morphometry (Stepanizer software, NIH ImageJ), to evaluate lung vascular remodeling and RV hypertrophy. Cardiomyocytes number, length and diameter were measured on digitized images of RV tissue slices. Cardiomyocytes volume was calculated by assuming a cardiomyocyte shape in the form of an elliptical cylinder. Results After 12 weeks of high-fat diet, both male and female EHITSN-KDITSN mice exhibited a significant increase, greater than 40%, in body weight compared to standard diet EHITSN-KDITSN mice, used for comparison. We found sex-specific responses to explain the effects of obesity on PAH pathology. Specifically, high-fat diet EHITSN-KDITSN female and male mice displayed significant lung vascular remodeling, with a greater number of vascular obliterative and plexiform lesions and greater muscularization of small (20µm- 50µm) and mid-size pulmonary arteries (50µm - 100µm) compared with the standard diet EHITSN-KDITSN mice. Hemodynamic measurements indicated higher right ventricular systolic pressure (RVSP) values for both male and female obese EHITSN-KDITSN mice compared with nonobese mice. However, obese EHITSN-KDITSN male mice showed slightly higher RVSP values compared to the female counterparts. While the high-fat diet did not trigger significant changes in RV hypertrophy regardless of obesity and PAH background, RV hypertrophy was greater in the obese EHITSN-KDITSN female mice vs. obese EHITSN-KDITSN males. WGA Alexa Fluor 594/DAPI staining to quantify the histological size and the number of cardiomyocytes indicated a greater cardiomyocytes hypertrophic response with about 30% increase in cell volume and a modest 15% increased number in the obese female EHITSN-KDITSN mice by comparison with the obese EHITSN-KDITSN males, suggesting that female mice are more prone to the effects of increased body fat mass. Conclusions Our studies demonstrate that high-fat diet-induced obesity drives sex-specific different disease profiles in the pulmonary vasculature and cardiac function of a murine model of pulmonary arterial hypertension. This abstract is funded by: RO1HL127022 to SP
Sharma et al. (2026) studied Pulmonary arterial hypertension. High-fat diet vs. Standard diet was evaluated on Lung vascular remodeling, lung hemodynamics, and cardiac function. A 12-week high-fat diet in a murine model of pulmonary arterial hypertension induced sex-specific responses, with obese females showing a 30% increase in cardiomyocyte volume compared to obese males.