Sex-dependent transcriptional and imaging responses to metformin in young-adult mice with SuHx-induced pulmonary arterial hypertension
- 1Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA) , ,
- 2University of the Basque Country (EHU) , ,
- 3CIBERES, ISCIII (CIBER, Carlos III Institute, Spanish Ministry of Sciences and Innovation) , ,
Abstract
Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterised by pulmonary vascular remodelling, right ventricular (RV) pressure overload, and ventricular metabolic reprogramming. Metformin has been proposed as a candidate therapy for PAH on the basis on encouraging preclinical results, most of which have been obtained in rat models and in single-sex cohorts. Its preventive effects in mice and its dependence on biological sex remain incompletely characterised. Based on the Sugen5416/hypoxia (SuHx) model, male and female mice were exposed to normoxia (Ctrl) or Sugen5416/Hypoxia (SuHx) conditions (PAH group) for 21 days, with two parallel groups, Ctrl + Met and PAH + Met, receiving metformin 0.25% w/v (effective dose 410–503 mg/kg/day) ad libitum in drinking water. The endpoints comprised cardiac cine and phase-contrast MRI, invasive RV systolic pressure (RVSP), Fulton index, [ ¹⁸ F]-FDG PET, glucose and fatty acid related RT-qPCRs, histology and weekly measured body weight. These experimental data suggested that SuHx reliably induced RV mass gain and elevated RVSP in both sexes. Also, metformin did not attenuate the primary structural or haemodynamic features of the model in either sex. In fact, metformin triggers sex- and ventricle-specific responses detectable at multiple levels: a opposite transcriptional changes in RV's Glut 4 between sexes, together with a coordinated downregulation of left ventricle (LV) fatty acid oxidation transcripts under both SuHx and metformin. Also, the histological analysis performed with WGA revealed that sex-specific cardiomyocyte hypertrophy phenotypes emerge only with metformin. Finally, the MRI determination of RV volumes and ejection fraction along with the pulmonary artery dilatation highlighted this sex-dysmorphism. Collectively, our data argue against a preventive benefit of metformin on the core SuHx-PAH phenotype in either male or female mice. Furthermore, they highlight cardiopulmonary and cellular markers that vary by sex and caution against the assumption that the beneficial effects of metformin in PAH models can be extrapolated without explicit confirmation stratified by sex.
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BibTeX
@article{fernandezfolgueral2026sexdependent,
title = {{Sex-dependent transcriptional and imaging responses to metformin in young-adult mice with SuHx-induced pulmonary arterial hypertension}},
author = {Irene Fernández-Folgueral and María Jesús Sánchez-Guisado and Irati Aiestaran-Zelaia and Marta Beraza and Aitor Zubillaga-Unsain and Claudia Miranda-Pérez de Alejo and Amanda Marrero-Pérez de Alejo and Kinsey Mae Thorpe and Angela Frimpong and Rui Adão and Ian J. Holt and Jesús Ruiz-Cabello},
journal = {Frontiers in cardiovascular medicine},
year = {2026},
month = oct,
doi = {10.3389/fcvm.2026.1947678},
url = {https://europepmc.org/article/PMC/PMC13690730},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sex-dependent transcriptional and imaging responses to metformin in young-adult mice with SuHx-induced pulmonary arterial hypertension
AU - Irene Fernández-Folgueral
AU - María Jesús Sánchez-Guisado
AU - Irati Aiestaran-Zelaia
AU - Marta Beraza
AU - Aitor Zubillaga-Unsain
AU - Claudia Miranda-Pérez de Alejo
AU - Amanda Marrero-Pérez de Alejo
AU - Kinsey Mae Thorpe
AU - Angela Frimpong
AU - Rui Adão
AU - Ian J. Holt
AU - Jesús Ruiz-Cabello
PY - 2026
DA - 2026/10/09
JO - Frontiers in cardiovascular medicine
DO - 10.3389/fcvm.2026.1947678
UR - https://europepmc.org/article/PMC/PMC13690730
AB - Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterised by pulmonary vascular remodelling, right ventricular (RV) pressure overload, and ventricular metabolic reprogramming. Metformin has been proposed as a candidate therapy for PAH on the basis on encouraging preclinical results, most of which have been obtained in rat models and in single-sex cohorts. Its preventive effects in mice and its dependence on biological sex remain incompletely characterised. Based on the Sugen5416/hypoxia (SuHx) model, male and female mice were exposed to normoxia (Ctrl) or Sugen5416/Hypoxia (SuHx) conditions (PAH group) for 21 days, with two parallel groups, Ctrl + Met and PAH + Met, receiving metformin 0.25% w/v (effective dose 410–503 mg/kg/day) ad libitum in drinking water. The endpoints comprised cardiac cine and phase-contrast MRI, invasive RV systolic pressure (RVSP), Fulton index, [ ¹⁸ F]-FDG PET, glucose and fatty acid related RT-qPCRs, histology and weekly measured body weight. These experimental data suggested that SuHx reliably induced RV mass gain and elevated RVSP in both sexes. Also, metformin did not attenuate the primary structural or haemodynamic features of the model in either sex. In fact, metformin triggers sex- and ventricle-specific responses detectable at multiple levels: a opposite transcriptional changes in RV's Glut 4 between sexes, together with a coordinated downregulation of left ventricle (LV) fatty acid oxidation transcripts under both SuHx and metformin. Also, the histological analysis performed with WGA revealed that sex-specific cardiomyocyte hypertrophy phenotypes emerge only with metformin. Finally, the MRI determination of RV volumes and ejection fraction along with the pulmonary artery dilatation highlighted this sex-dysmorphism. Collectively, our data argue against a preventive benefit of metformin on the core SuHx-PAH phenotype in either male or female mice. Furthermore, they highlight cardiopulmonary and cellular markers that vary by sex and caution against the assumption that the beneficial effects of metformin in PAH models can be extrapolated without explicit confirmation stratified by sex.
SN - 2297-055X
ER -