Impact of Aging and G Protein‐Coupled Estrogen Receptor Deletion in Arterial Stiffening and Cardiac Function in Male and Female Mice

Abstract

Arterial stiffening assessed by pulse wave velocity (PWV) independently predicts cardiovascular events and is exacerbated in aging men and women. Our previous studies demonstrated that G protein‐coupled estrogen receptor (GPER) plays a protective role in the heart and vasculature. The current study evaluated sex differences and the impact of GPER and aging on arterial stiffening and cardiac function. We hypothesized that genetic deletion of GPER induces sex differences in arterial stiffness and cardiac function during aging. Male and female wildtype (wt) and global GPER knockout (ko) mice were used between 4–6 months (adult) and 12–13 months (middle‐aged; n=6–17 per group). Echocardiography was performed under isoflurane anesthesia in short axis view to assess cardiac function, and local PWV was obtained within the carotid artery. Data was subjected to 3‐way ANOVA and correlation analysis. PWV was significantly higher in adult male ko versus wt mice (1.60 ± 0.07 m/s vs. 1.21 ± 0.05 m/s, P<0.001) but was not altered by GPER deletion in female mice. Aging significantly increased PWV (P<0.0001) in both males and females. PWV did not correlate with ejection fraction (P=0.69) or heart rate (P=0.89) but inversely correlated with early left ventricular filling deceleration time (Edec time; P=0.0005, r= −0.37) and left ventricular ejection time (LVET; P=0.044, r= −0.22) and positively correlated with relative wall thickness (RWT; P=0.008, r= 0.281). In conclusion, GPER deletion impacted PWV in adult male mice, while aging increased PWV in all groups. Future studies will investigate whether other pathological conditions such as hypertension reveal a phenotype of vascular stiffness in female GPER ko mice. The inverse relationship between PWV and Doppler‐derived indices of left ventricular distensibility underscores the important relationship between arterial and cardiac stiffness.Support or Funding InformationNIH Grant # R01HL133619 to SHL