Metabolic dysfunction-associated steatohepatitis (MASH) confers a superimposed risk to develop cardiovascular disease (CVD), independently of the cardiometabolic risk factors. The pathogenic mechanisms supporting a liver-to-CVD axis remain unknown. Endothelial dysfunction is characterized by an imbalanced endothelium-production of protective vs. deleterious factors that promote a pro-constrictive phenotype. It is the earliest feature of atherosclerosis and hypertension contributing to major CV events.

This study aims to characterize the vascular system with a special focus on endothelial function in a murine model of MASH disease.

Male Foz mice fed with high fat diet (HFD) for 24 weeks were used as a model of MASH. Blood pressure was monitored over 24h using telemetry. Endothelial function was evaluated in the first-order mesenteric arteries by wire myograph measurements. Blood nitrosylated hemoglobin (HbNO) was quantified by electron paramagnetic resonance. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, was measured using ELISA. Western blot analysis and qPCR were conducted to investigate the NO pathway.

Despite the absence of atherosclerotic plaques and hypertension, HFD-fed Foz mice (FH) exhibit endothelium-dependent impaired relaxation compared to the dysmetabolic controls (HFD-fed littermates). We demonstrated reduced NO-dependent vasodilatation in response to carbachol in FH compared to controls (Fig. 1). Consistent with these findings, our results indicate reduced expression and activation of aortic endothelial nitric oxide synthase (eNOS) associated with higher plasma ADMA in FH (Fig. 1). However, there is no difference in blood HbNO between the two groups. The hepatic expression of inducible NO synthase (iNOS), induced by inflammation as seen in MASH liver, is significantly increased in FH (fold change 15).

Our results demonstrate that mice with MASH but not the dysmetabolic controls present endothelial dysfunction characterized by impaired NO-dependent vasodilation. This dysfunction may be attributed in part to lower expression and activation of eNOS and elevated plasma ADMA level. Our data further suggest that the inflamed liver could contribute to the disruption of NO balance by the upregulating iNOS, thereby disturbing systemic NO production.