Nebivolol Protects the Thoracic and Abdominal Aorta and Their Perivascular Adipose Tissue From the Differential Detrimental Effects of Obesity

Abstract

The effects of obesity on the vasculature and perivascular adipose tissue (PVAT) function vary according to the vascular territory. Nebivolol is a third-generation β-blocker that exerts vasculoprotective effects in obesity. The thoracic and abdominal aorta show different responses under physiological conditions, and their PVATs have a distinctive composition and secretory profile. We hypothesized that obesity would affect thoracic and abdominal aortic responsiveness, as well as their PVAT function, differently and that nebivolol would restore obesity-induced vascular and PVAT changes. To test this hypothesis, male Wistar Hannover rats were fed a hypercaloric diet for 14 weeks. Nebivolol (10 mg/kg/day) was administered via gavage during the last 4 weeks. Obesity increased superoxide (O₂•⁻) generation within the thoracic PVAT, but this response did not result in a loss of its anticontractile effect. Vascular hypercontractility was detected in thoracic aortas, which was mediated by the overproduction of NADPH oxidase-derived O₂•⁻ and reduced nitric oxide (NO) bioavailability. Conversely, obesity induced a pro-contractile phenotype in the PVAT of the abdominal aorta. This response occurred in an endothelium-dependent manner, was ameliorated by tiron, and was accompanied by increased O₂•⁻ levels. In all cases, nebivolol reversed the effects of obesity. In summary, obesity differentially affects the thoracic and abdominal aorta and their respective PVATs. Nebivolol exerts vasculoprotective effects through antioxidant mechanisms, leading to a reversal of obesity-induced vascular hypercontractility in both aortic segments. The beneficial effects of nebivolol described here could help mitigate cardiovascular complications associated with obesity. Obesity induces PVAT dysfunction. Extending this knowledge, we demonstrated that obesity differentially affects the thoracic and abdominal aorta along with their associated PVATs. This widespread impairment of PVAT function can drive various adverse vascular consequences, including arterial hypertension and aneurysm formation. Critically, peri-aortic PVAT is of particular clinical relevance due to its association with metabolic risk factors and vascular calcification. Nebivolol exerts vasculoprotective effects via antioxidant mechanisms within PVAT, ultimately reversing obesity-induced vascular hypercontractility in both aortic segments. Thus, investigating pharmacological agents that restore PVAT function, as demonstrated here with nebivolol, represents a promising therapeutic strategy to mitigate obesity-related cardiovascular complications.