Sex-Dependent Differences in Pulmonary Vascular Resistance, Impedance, and Distensibility Revealed by Impaired Shear Stress Mechanotransduction

Sex-dependent differences in pulmonary vascular mechanics have been reported in both healthy and diseased populations, yet the mechanisms contributing to these differences remain poorly defined. Differences in shear stress responsiveness by the pulmonary endothelial surface may contribute to these differences in mechanics. This study investigated sex differences in shear stress responsiveness by measuring pulmonary pressure-flow relationships in isolated perfused lungs from male and female C57BL/6J mice. Pressure-flow relationships were measured under steady and pulsatile flow conditions before and after treatment with heparinase I to impair shear stress mechanotransduction. Pulmonary vascular resistance (PVR), vascular impedance, wave reflectance (RW), and pulmonary vascular distensibility (a) were quantified from pressure-flow data. Prior to treatment, male and female lungs exhibited comparable pulmonary vascular mechanics. Following heparinase I treatment, female lungs demonstrated significantly greater increases in PVR, 0-Hz impedance (Z0), and RW than male lungs. In contrast, characteristic impedance (ZC) remained unchanged in both sexes post-treatment compared to pre-treatment, indicating preservation of proximal conduit arterial mechanics. Female lungs also exhibited reduced distensibility than males, suggesting reduced pulmonary vascular adaptation to increasing flow. These findings indicate that impaired shear stress mechanotransduction had a greater impact in females than males and predominantly affected distal pulmonary vascular function while preserving proximal arterial properties. Our findings reveal sex differences in pulmonary vascular function with impaired shear stress mechanotransduction. These findings highlight the importance of considering sex as a biological variable in studies of pulmonary vascular biomechanics and vascular adaptation to flow.