Sex-Specific Variations in Vascular Properties Across Pulmonary and Systemic Circulations

Introduction: Many cardiovascular diseases show sex specific differences in severity and incidence. For instance, reproductive age females have a lower incidence of systemic hypertension compared to males. and more favorable outcomes compared to males. In contrast, for pulmonary hypertension (PH), younger females have a higher incidence, though males tend to experience worse clinical outcomes. The underlying physiological mechanisms responsible for these sex- and vascular bed-specific disparities remain poorly understood, in part because baseline differences in vessel properties between the pulmonary and systemic vascular beds remain incompletely defined. This study seeks to characterize the baseline sex differences in vascular properties across the pulmonary and systemic vascular beds. Methods: Using male and female wild-type wistar Kyoto rats, we evaluated the ex-vivo mechanical properties of the pulmonary artery (PA) and aorta using uniaxial mechanical testing. Endothelial-dependent and -independent vasorelaxation responses were assessed by administering varying concentrations of acetylcholine (Ach) and sodium nitroprusside (SNP), respectively. These experiments were conducted both with and without the application of indomethacin to elucidate COX's role in modulating vascular function. Results: Female PAs exhibit higher stiffness compared to age-matched males, but no significant male-female differences were detected in the aorta. Specifically, female PAs displayed a steeper stress-strain relationship, higher incremental modulus in the collagen-mediated range, and a lower strain at failure when compared to male counterparts. Vascular reactivity data for the PAs showed that endothelial-dependent maximal relaxation elicited by acetylcholine was amplified with COX inhibition in both sexes. In contrast, while male and female aortas had similar maximum relaxation for Ach-induced responses at baseline, COX inhibition elicited a increase in maximal relaxation only in female aortas. In the case of endothelial-independent vasorelaxation, female samples achieved significantly higher maximum relaxation than male samples in both PAs and aortas under baseline conditions. Notably, female aortas also exhibited a significantly lower EC50 value compared to males at baseline, a difference that was absent in the PAs. Following COX inhibition, the observed sex-based differences in maximum relaxation disappeared in both the PA & aorta and resulted in a reduction in EC50s of the aorta for both sexes. Discussion: Our findings indicate that sex differences in vascular mechanics and function are distinct in the systemic vs. pulmonary circulation. Female PAs are stiffer than their male counterparts at baseline, which may contribute to the higher incidence of PH in females. Despite this increased stiffness, female PAs exhibit greater SMC-dependent vasorelaxation, possibly as a compensatory mechanism to maintain normal hemodynamics. Additionally, COX was identified as a contributor to Ach-induced vasoconstriction in both male and female PAs. However, in the aorta, COX was found to be involved in Ach-induced vasoconstriction only in females. Finally, in the case of the SNP response, COX may be inducing a vasoconstrictive response only in the male PAs and aortas. Our results offer a foundation for further studies to explore how sex differences impact the progression of cardiovascular diseases. Acknowledgements: ChatGPT (Version GPT-4) was used for rephrasing some sections to enhance clarity and readability. The tool was used in a manner that does not conflict with APS ethical policies, and the authors take full responsibility for the content. R01HL148112 (L.S.); R01HL151530 (K.S.) This abstract was presented at the American Physiology Summit 2025 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.