Sex-Specific Response to Endothelin-1 Overexpression Mediates Thoracic Aortic Aneurysm Development

Introduction: Thoracic aortic aneurysms (TAAs) are common diseases associated with high morbidity and mortality. Although TAAs are more common in men, women have worse outcomes and dissect at smaller aortic diameters. Endothelin-1 (ET-1) is the most potent vasoconstrictor in humans, and an important mediator of vascular stiffness and tone. ET-1 levels are increased in patients with TAA, and genetic variants that affect ET-1 production and receptor expression are associated with vascular diseases. Though ET-1 levels do not differ between men and women with TAA, it is unknown if response to ET-1 mediates sex-specific differences. Hypothesis: ET-1 has different effects on vascular stiffness and aortic dissection risk in men and women. Methods: Angiotensin-II (AngII) was delivered subcutaneously at 1 ug/kg/min dose and rate using osmotic pumps for 28 days in endothelial cell-specific ET-1 transgenic (eET-1) and matched WT control mice. We measured blood pressure, aortic stiffness, and aortic size at the end of the study. Results: We observed marked sex-specific ET-1 effects on TAA. Despite elevated blood pressure in all animals that received AngII (Fig1A), we observed increased aortic stiffness in male eET-1 mice (+1.5 m/s eET-1 vs. +0.74 m/s WT) but decreased aortic stiffness in female eET-1 mice (-1.9 m/s eET-1 vs. +0.69 m/s WT), measured by pulse wave velocity (Fig1B). Consistent with these results, aortic diameter was only increased in male eET-1 mice (+0.61 mm eET-1 vs. +0.11 mm WT) but not in female eET-1 mice (+0.06 mm eET-1 vs. +0.11 mm WT) (Fig1C). Significantly, 2 of 3 male eET-1 animals died before 28 days from dissected TAAs, whereas all females survived the length of the study. Conclusions: In the AngII-TAA model, there is a sex dimorphic effect of ET-1 overexpression. Male mice have greater vascular stiffness and develop TAA in response to the same level of ET-1 as in matched female mice. This difference may explain the increased incidence of TAA in men.