Sex and the G Protein–Coupled Estrogen Receptor Impact Vascular Stiffness

Abstract

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.