Mikala Mueller, Sue Gu, Krithika Lingappan, R Blair Dodson, Chelsea M. Magin
We synthesize emerging evidence demonstrating sex-dependent differences in pulmonary vascular remodeling, right ventricular adaptation, extracellular matrix composition, and cellular responses to mechanical and hormonal cues.
Sex differences shape disease susceptibility, progression, and therapeutic response across human health, yet their systematic integration into biomedical research remains uneven. In preclinical studies, animals of only one sex are frequently used, the sex of primary cells is often unreported or inconsistently documented, and experiments are rarely powered or analyzed to detect sex-specific effects. These limitations are particularly consequential in pulmonary arterial hypertension (PAH), a disease marked by pronounced sexual dimorphism. PAH disproportionately affects females, while males exhibit worse right ventricular function and survival, implicating complex biological mechanisms driven by sex chromosomes, hormones, and genetic and epigenetic regulation. Persistent gaps in sex-based reporting and analysis continue to impede mechanistic insight, reproducibility, and translational progress. This Perspective calls for a systematic shift in pulmonary vascular research toward rigorous integration of sex as a biological variable (SABV). We synthesize emerging evidence demonstrating sex-dependent differences in pulmonary vascular remodeling, right ventricular adaptation, extracellular matrix composition, and cellular responses to mechanical and hormonal cues. We highlight how unreported sex of cells, animals, and biological reagents such as hormone-containing sera introduces hidden bias and limits reproducibility. Advances in biomaterials, genetically informed animal models, and hormone-aware experimental systems now offer new opportunities to interrogate SABV mechanistically. Finally, we propose a practical framework to improve transparency, including standardized sex-based metadata, sex disaggregated data sharing, and SABV aware analytical and computational approaches. Recognizing sex as a fundamental biological variable will enhance rigor and accelerate discovery, supporting the development of more precise and effective therapies for pulmonary vascular disease.