Angiotensin (1–7) production increases during AT1R (angiotensin type-1 receptor) blockade. The contribution of Ang (1–7) (angiotensin [1–7]) and its receptor (MasR) to the favorable effect of angiotensin receptor blockers on remodeling and function of resistance arteries remains unclear. We sought to determine whether MasR contributes to the improvement of vascular structure and function during chronic AT1R blockade. Spontaneously hypertensive rats were treated with Ang (1–7) or olmesartan ± MasR antagonist A-779, or vehicle, for 14 days. Blood pressure was measured by tail cuff methodology. Mesenteric arteries were dissected and mounted on a pressurized micromyograph to evaluate media-to-lumen ratio (M/L) and endothelial function. Expression of MasR and eNOS (endothelial nitric oxide synthase) was evaluated by immunoblotting, plasma nitrate by colorimetric assay, and reactive oxygen species production by dihydroethidium staining. Independently of blood pressure, olmesartan significantly reduced M/L and improved NO bioavailability, A-779 prevented these effects. Likewise, Ang (1–7) significantly reduced M/L and NO bioavailability. MasR expression was significantly increased by Ang (1–7) as well as by olmesartan, and it was blunted in the presence of A-779. Both Ang (1–7) and olmesartan increased eNOS expression and plasma nitrite which were reduced by A-779. Superoxide generation was attenuated by olmesartan and Ang (1–7) and was blunted in the presence of A-779. These MasR-mediated actions were independent of AT2R activation since olmesartan and Ang (1–7) increased MasR expression and reduced M/L in Ang II (angiotensin II)–infused AT2R knockout mice, independently of blood pressure control. A-779 prevented these effects. Hence, MasR activation may contribute to the favorable effects of AT1R antagonism on NO bioavailability and microvascular remodeling, independently of AT2R activation and blood pressure control.

Endothelial dysfunction represents the critical pathophysiological mediator linking the modern epidemics of obesity, type 2 diabetes mellitus, and cardiovascular disease. Persistent hyperglycemia and metabolic dysregulation promote oxidative stress, reduce nitric oxide bioavailability, and activate inflammatory pathways, thereby accelerating atherosclerosis and cardiovascular complications. Therefore, strategies aimed at restoring endothelial function are crucial to mitigate cardiovascular complications in individuals with cardiometabolic disorders. Among antidiabetic therapies, glucagon-like peptide-1 receptor agonists have demonstrated cardiovascular benefits in large-scale outcome trials, but the underlying mechanisms remain only partially elucidated. In this mini-review, we critically examine both clinical and experimental evidence, with emphasis on the direct effects of glucagon-like peptide-1 receptor agonists on endothelial function. Moreover, we address the heterogeneity within this drug class, noting how differences may contribute to variability in vascular outcomes. By integrating clinical findings with molecular data, this review aims to refine our understanding of the potential endothelial mechanisms underlying cardiovascular protection. Our critical synthesis provides a clearer framework for interpreting the vascular effects of glucagon-like peptide-1 receptor agonists beyond glycemic control, thereby offering a more comprehensive view of their role in managing cardiometabolic disease.

Cardiovascular diseases (CVDs) still represent the greatest burden on healthcare systems worldwide. Despite the enormous efforts over the last twenty years to limit the spread of cardiovascular risk factors, their prevalence is growing and control is still suboptimal. Therefore, the availability of new therapeutic tools that may interfere with different pathophysiological pathways to slow the establishment of clinical CVDs is important. Previously, the inhibition of neurohormonal systems, namely the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system, has proven to be useful in the treatment of many CVDs. Attempts have recently been made to target an additional hormonal system, that of the natriuretic peptides (NPs), which, when dysregulated, can also play a role in the development CVDs. Indeed, a new class of drug, the angiotensin receptor–neprilysin inhibitors (ARNi), has the ability to counteract the effects of angiotensin II as well as to increase the activity of NPs. ARNi have already been proven to be effective in the treatment of heart failure with reduced ejection fraction. New evidence has suggested that, in the next years, the field of ARNi application will widen to include other CVDs, such as heart failure, with preserved ejection fraction and hypertension.

Since December 2019, a new coronavirus, named SARS-CoV-2, has spread globally, affecting >200 000 people worldwide with the so-called COVID-19 disease. The scientific community is actively and constantly working to identify the mechanisms involved in the diffusion of this virus and the pathogenesis of the infection, with its most frequent and severe complication, namely interstitial pneumonia. To date, SARS-CoV-2 is known to enter the host cells via the angiotensin-converting enzyme 2 protein. For this reason, the hypothesis that drugs capable of increasing the expression of this protein may have a role in the spread of the virus and in the symptomatology of affected patients has taken hold. The purpose of this Editorial is to briefly show the evidence currently available in this regard and to provide ideas for future research.