Absence of Endothelial Estrogen Receptor Alpha Decreases Stiffness and Induces Outward Hypertrophic Remodeling in the Resistance Arteries of Male Mice Fed a Western Diet
Authors: Ramirez‐Perez Francisco I. , Manrique‐Acevedo Camila , Padilla Jaume , Vieira‐Potter Victoria J. , Annaya Aroor R. , Barron Brady J. , Chen Dongqing , Haertling Dominic , Declue Cory , Sowers James R. , Martinez‐Lemus Luis A. 
Published: November 2023

Consumption of diets high in fat and fructose (Western diet, WD) is associated with the alarming prevalence of obesity, insulin resistance, type 2 diabetes and cardiovascular disease. We have previously demonstrated that WD feeding in female mice results in conduit artery endothelial dysfunction, vascular remodeling and augmented stiffness. In addition, due to its potential cardiovascular protective effects, we recently examined the role of endothelial cell (EC) estrogen receptor alpha (ERα) signaling on vascular stiffness in obese insulin‐resistant female mice. Against our expectations, we found that female mice lacking EC‐ERα (EC‐ERαKO) were protected against WD‐induced vascular stiffness. However, whether these paradoxical findings translate to males is not known. We hypothesized that, similar to females, blunting EC‐ERα signaling in male mice fed a WD would result in reduced arterial stiffness. To test this hypothesis, we used ERα floxed (ERαFl2, controls) and EC‐ERαKO mice (n=6–8 per group). At 8 weeks of age, mice were fed a WD (fat 46%, high carbohydrate as sucrose 17.5% and high fructose corn syrup 17.5%) for 20 weeks. Mice were sacrificed at 28 weeks of age and their mesenteric resistance arteries were collected to determine presence of functional, mechanical and structural changes between the two genetically distinct groups. We did not observe any differences between the groups in their functional responses to phenylephrine, acetylcholine or sodium nitroprusside. EC‐ERαKO mice had mesenteric resistance arteries with larger internal diameters (p<0.05) indicative of outward remodeling, as well as with increased wall cross‐sectional area (p<0.05), and mean wall thickness (p<0.05) indicative of hypertrophic remodeling compared with those of ERαFl2 control mice. We also observed an increase in both elastin (p<0.05) and collagen (p<0.05) content in the arteries of EC‐ERαKO vs. those of controls, but there was no difference in the arterial elastin‐to‐collagen ratio between the groups. The number of fenestrae present in the internal elastic lamina of mesenteric arteries from EC‐ERαKO mice decreased (p<0.05), while the area per fenestra increased (p<0.05), when compared to those from ERαFl2 mice. This was associated with a tendency for EC‐ERαKO vessels to have an increased elastic moduli normalized as a function of the percolation of the internal elastic lamina. In addition, EC‐ERαKO vessels had decreased incremental moduli of elasticity (p<0.05) and increased compliance (p<0.05). We conclude that in male mice fed a WD, ablation of EC‐ERα signaling has beneficial effects to vascular health, decreasing arterial stiffening and inducing outward hypertrophic remodeling in resistance arteries.Support or Funding InformationThis work was supported by National Institutes of Health Grants K08HL129074‐01 (to C.M.), VA I01 BX001981/BX/BLRD (to J.R.S), NIH K01HL‐125503 and R21DK‐105368 (to J.P.), and NIH R01 HL‐088105 (to L.A.M.).