Indices of vascular aging were different in male and female mice. Sex differences in pulse wave velocity, blood pressure, and large artery stiffness were abrogated in middle-aged mice, but the female advantage in resistance artery vasodilator function was maintained. GPER deletion abrogated these sex differences and significantly reduced endothelial function in adult female mice. Additional studies are needed to characterize sex differences in vascular aging to personalize early detection and treatment for vascular diseases.

Because arterial stiffness increases following menopause, estrogen may be a protective factor. Our previous work indicates that the GPER (G protein–coupled estrogen receptor) mediates estrogen’s vascular actions. In the current study, we assessed arterial stiffening using pulse wave velocity (PWV), a clinically relevant measurement that independently predicts cardiovascular mortality. We hypothesized that genetic deletion of GPER would attenuate sex differences in PWV and would be associated with changes in passive vascular mechanics. Control and Ang II (angiotensin II)–infused male and female wild-type and GPER knockout mice were assessed for blood pressure, intracarotid PWV, cardiac function, passive biaxial mechanics, constitutive modeling, and histology. Sex differences in PWV and left ventricular mass were detected in wild-type mice but absent in GPER knockout and Ang II–infused mice, regardless of genotype. Despite lower PWV, the material stiffness of female wild-type carotids was greater than males in control conditions and was maintained in response to Ang II due to increased wall thickness. PWV positively correlated with unloaded thickness as well as circumferential and axial stiffness only in females. In contrast, blood pressure positively associated with circumferential and axial stiffness in males. Taken together, we found that female wild-type mice were unique in their vascular adaptation to hypertension by increasing wall thickness to maintain stiffness. Given that carotid arteries are easily accessible clinically, systematic assessment of intracarotid PWV in women may provide insight into vascular damage that cannot be assumed from blood pressure measurements alone.

BACKGROUND: Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging and whether activation of the G-protein–coupled estrogen receptor could reverse stiffness. METHODS: Female C57Bl/6J mice were ovariectomized at 10 weeks of age or aged to 52 weeks, and some mice were treated with G-protein–coupled estrogen receptor agonists. RESULTS: Ovariectomy and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while ovariectomy increased material stiffness without altering vascular geometry. RNA-sequencing analysis revealed that ovariectomy downregulated smooth muscle contractile genes. The enantiomerically pure G-protein–coupled estrogen receptor agonist, LNS8801, reversed stiffness in ovariectomy mice to a greater degree than the racemic agonist G-1. In summary, ovariectomy and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling, while ovariectomy-induced material stiffness independent of geometry and a loss of the contractile phenotype. CONCLUSIONS: This study enhances our understanding of the impact of estrogen loss on vascular health in a murine model and warrants further studies to examine the ability of LNS8801 to improve vascular health in menopausal women. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04130516.

This study reveals that ANG II-induced hypertension disrupts the circadian rhythm of blood pressure in both male and female mice, with parallel effects on vascular clock gene and estrogen receptor diurnal patterns. Notably, sex-specific responses to hypertension in terms of locomotor activity, heart rate, and baroreflex sensitivity are revealed. These findings pave the way for chronotherapeutic strategies tailored to mitigate cardiovascular risks associated with disrupted circadian rhythms in hypertension.