Background:
Women with obesity, insulin resistance and type 2 diabetes mellitus (T2D) lose the cardiovascular disease protection normally afforded by female sex hormones, but the underlying mechanism(s) remain unknown. Increases in vascular stiffness occur with aging, but conditions of insulin resistance such as obesity and T2D are characterized by accelerated development of this phenomenon. Under physiological conditions, vascular estrogen signaling via estrogen receptor alpha (ERα) increases endothelial bioavailable nitric oxide which decreases stiffness. Nevertheless, in conditions of insulin resistance, the effects of ERα signaling may be deleterious.
Methods:
We used a novel rodent model lacking ERα in the endothelial cells (ECERαKO). The genomic region encompassing exon 3 of the ERα gene was flanked by loxP sites. ECERαKO mice were generated by crossing ERα doubled floxed mice with Cad-Cre+ mice (VE-Cadherin promoter driving expression of Cre-recombinase). Female ECERαKO mice and littermates were fed a high fructose/high sucrose (Western diet - WD) for 8 weeks. The WD diet consisted of 60% fat and 20% sucrose. At the end of the intervention period, mice underwent in vivo and ex vivo assessment of vascular stiffness.
Results:
The absence of EC ERα did not impact whole body insulin sensitivity (examined by HOMA-IR). Females lacking the endothelial specific ERα had less vascular stiffness when assessed in vivo via aortic pulse wave velocity than the littermates fed with a WD (3.43 ± 0.184 m/s vs. 4.080 ± 0.172 m/s, p<0.05). Similarly, ex vivo evaluation of aortic endothelial cell stiffness using atomic force microscopy (AFM) revealed increased stiffness in the females with intact EC ERα when compared with ECERαKO females (1.91 ± 0.60 kPa vs. 13.09 ± 2.61 kPa ) (p<0.05). Resistant vessel (femoral artery) also revealed less stiffness (decreased modulus of elasticity) in ECERαKO mice fed a WD.
Conclusion:
Endothelial ERα does not protect females from vascular stiffness induced by a WD. Indeed, the present data suggest a predisposition toward protection of rodent lacking ERα in conditions of insulin resistance.
Activation of Penile Proadipogenic Peroxisome Proliferator-Activated Receptor with an Estrogen: Interaction with Estrogen Receptor Alpha during Postnatal Development
