Over-nutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption of a western diet (WD) containing excess fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks resulted in cardiac diastolic dysfunction and aortic stiffening in young female mice and that these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies by testing whether WD-induced diastolic dysfunction, and factors contributing to diastolic impairment, such as cardiac fibrosis, hypertrophy, inflammation and impaired insulin signaling, are modulated by excess endothelial cell mineralocorticoid receptor (ECMR) signaling. Four week-old female ECMR knockout and wild type mice were fed mouse chow or WD for 4 months. WD feeding resulted in prolonged relaxation time, impaired diastolic septal wall motion and increased left ventricular (LV) filling pressure indicative of diastolic dysfunction. This occurred in concert with myocardial interstitial fibrosis and cardiomyocyte hypertrophy that was associated with enhanced pro-fibrotic (TGF-β1/Smad) and pro-growth (S6 kinase-1) signaling, as well as myocardial oxidative stress and a pro-inflammatory immune response. WD also induced cardiomyocyte stiffening, assessed ex vivo using atomic force microscopy. Conversely, ECMR deficiency prevented WD-induced diastolic dysfunction, pro-fibrotic and pro-growth signaling, in conjunction with reductions in macrophage pro-inflammatory polarization and improvements in insulin metabolic signaling. Therefore, our findings indicate that increased ECMR signaling associated with consumption of a WD plays a key role in activation of cardiac pro-fibrotic, inflammatory and growth pathways that lead to diastolic dysfunction in female mice.

Arteriolar vasoreactivity tightly regulates tissue-specific blood flow and contributes to systemic blood pressure (BP) but becomes dysfunctional in the setting of cardiovascular disease. The mineralocorticoid receptor (MR) is known to regulate BP via the kidney and by vasoconstriction in smooth muscle cells. Although endothelial cells (EC) express MR, the contribution of EC-MR to BP and resistance vessel function remains unclear. To address this, we created a mouse with MR specifically deleted from EC (EC-MR-KO) but with intact leukocyte MR expression and normal renal MR function. Telemetric BP studies reveal no difference between male EC-MR-KO mice and MR-intact littermates in systolic, diastolic, circadian, or salt-sensitive BP or in the hypertensive responses to aldosterone +/− salt or angiotensin II (AngII) +/− L-NAME. Vessel myography demonstrated normal vasorelaxation in mesenteric and coronary arterioles from EC-MR-KO mice. After exposure to AngII-induced hypertension, impaired endothelial-dependent relaxation was prevented in EC-MR-KO mice in mesenteric vessels but not in coronary vessels. Mesenteric vessels from AngII-exposed EC-MR-KO mice showed increased maximum responsiveness to Ach compared to MR-intact vessels, a difference that is lost with indomethacin+L-NAME pretreatment. These data support that EC-MR plays a role in regulating endothelial function in hypertension. Although there was no effect of EC-MR deletion on mesenteric vasoconstriction, coronary arterioles from EC-MR-KO mice showed decreased constriction to endothelin-1 and thromboxane agonist at baseline and also after exposure to hypertension. These data support that EC-MR participates in regulation of vasomotor function in a vascular bed-specific manner that is also modulated by risk factors such as hypertension.