Aging and G Protein‐Coupled Estrogen Receptor Exacerbates Carotid Artery Structural Remodeling

Abstract

Aging is a nonmodifiable risk factor for cardiovascular disease associated with arterial stiffening and cardiac dysfunction. We previously showed an important role for G protein‐coupled estrogen receptor (GPER) in modulating female protection from arterial stiffening. In this study, we hypothesized that aging would decrease vascular compliance in GPER knockout (ko) mice to a greater extent than wildtype (wt) mice. Adult (25 weeks) and middle‐aged (57 weeks) mice were subjected to high frequency ultrasound for pulse wave velocity (PWV), and structural remodeling in the carotid artery was assessed with biaxial pressure myography followed by constitutive modeling. Data was analyzed by 3‐way ANOVA and Sidak’s post hoc tests. As we previously showed, PWV was significantly lower in adult female wt mice versus their male counterparts (1.4 ± 0.05 vs. 1.1 ± 0.02 m/s; P=0.0004) but was not different in adult ko mice (1.6 ± 0.07 vs 1.4 ± 0.08, P=0.20). Interestingly, PWV increased with aging in female but not male wt mice, so that the sex difference was lost (1.7 ± 0.03 vs 1.7 ± 0.06, P=0.99). Despite the lower PWV, circumferential linearized material stiffness in passive conditions was elevated in adult female wt versus male wt (1.9 ± 0.2 vs. 1.4 ± 0.2 MPa; P=0.02), but this sex difference was lost in middle‐aged wt mice (1.3 ± 0.1 vs. 1.2 ± 0.1 MPa; P=0.87). Aging significantly increased the ratio of thick to thin collagen only in male wt and female ko groups. We found that females but not males experience an increase in PWV at middle‐age along with a decrease in circumferential stiffness. In contrast, female GPER mice already display a higher PWV as adults, indicating that GPER deletion in females is a model of accelerated vascular aging.