Absence of Endothelial Estrogen Receptor Alpha Decreases Arterial Stiffness and Induces Hypertrophic Remodeling in Angiotensin II infused Female Mice
Authors: Ramirez‐Perez Francisco I. , Lising Alexander M. , Lastra Guido , Manrique‐Acevedo Camila , Martinez‐Lemus Luis A. 
Published: June 2021

Vascular stiffening increases the risk of stroke, diastolic heart failure and chronic kidney disease, and is an early biomarker of cardiovascular disease (CVD), the leading cause of death worldwide. Although stiffening of the arteries is a naturally occurring phenomenon that appears with aging, conditions such as obesity and type 2 diabetes accelerate its appearance, particularly in women. Under physiological conditions, estrogen signaling via estrogen receptor alpha (ERα) increases nitric oxide in the endothelium and decreases vascular stiffness. However, estrogen therapy has failed to demonstrate beneficial cardiovascular effects in large clinical trials. We have previously demonstrated that under conditions of over‐nutrition, knockout (KO) of endothelial cell (EC) ERα in obese insulin‐resistant female mice results in reduced arterial stiffness. Given the central role that activation of the Renin‐Angiotensin‐System (RAS) has in the development of CVD, in the present study we studied the effects of Angiotensin II (AngII) infusion in EC‐ERαKO female mice on vascular stiffness. KO and wild type (control) littermates (n=8 per group) were treated with AngII (500 ng/kg/min) via osmotic mini‐pumps for 4 weeks. At the end of the intervention, the mice underwent in‐vivo assessment of vascular stiffness via aortic pulse wave velocity (PWV) and body weight was recorded. The mice were sacrificed at 28 weeks of age and vasomotor function determined in aortic rings using wire myography, while vascular mechanics were assessed in femoral arteries using pressure myography. No differences in body weight, aortic PWV were observed between groups (n=8 per group). No differences were observed either on the functional responses of aortic rings to acetylcholine or sodium nitroprusside between the groups (n=5 per group). However, with regard to the remodeling of femoral arteries, mice lacking ERα had increased wall cross‐sectional area (maximal difference at 120 mmHg, 34.632±4.960 vs. 20.793±1.827 × 103 μm2, p<0.05) and wall‐to‐lumen ratio (maximal difference at 5 mmHg, 0.559±0.026 vs. 0.457±0.028, p<0.05) vs. controls (n=7–8 per group). Furthermore, the mechanical properties of femoral arteries of EC‐ERαKO mice had decreased modulus of elasticity (maximal difference at 120 mmHg, 6.428±0.552 vs. 9.807±1.182 × 106 dynes/cm2, p<0.05) and increased cross‐sectional compliance (maximal difference at 40 mmHg, 8.893±1.130 vs. 3.974±0.825182 × 10−9 cm4/dynes, p<0.05) vs. controls (n=7–8 per group). We did not observe any differences in lumen diameter between the groups. These results suggest that in obese, insulin‐resistant female mice, ablation of EC‐ERα signaling in the setting of RAS activation confers beneficial effects to vascular health by decreasing the stiffness and inducing hypertrophic remodeling of mid‐sized arteries.Support or Funding InformationThis work was supported by National Institutes of Health Grants K08HL129074 (to C.M.), K08HL132012 (to G.L) and NIH R01 HL‐088105 (to L.A.M.‐L.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.