As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116–734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals ( P =0.02). The vasorelaxing response to canagliflozin was not modified ( P =0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by H 2 O 2 scavenging (catalase); also, canagliflozin-induced relaxation was similar ( P =0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na + /H + exchanger 1 inhibitor BIX ( P =0.67), but greater than that to the Na + /Ca ++ exchanger inhibitor SEA 0400 ( P =0.001), hinting a role of Na + /H + exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide ( P =0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.

Obesity associates with premature atherosclerosis and an increased burden of cardiovascular disease, especially when accompanied by abnormalities of lipid and glucose metabolism. Angiopoietin-like (ANGPTL)3 and ANGPTL4 are metabolic regulators, whose upregulation is associated with dyslipidemia, insulin resistance and atherosclerosis. We analyzed, therefore, changes in circulating ANGPTL3 and ANGPTL4 in obese patients with different metabolic phenotypes and their relation with impaired vasodilator reactivity, an early abnormality in atherosclerosis. Compared to the lean subjects (n = 42), circulating ANGPTL3 was elevated (both p > 0.001) in the patients with metabolically unhealthy obesity (MUO; n = 87) and type 2 diabetes (T2D; n = 31), but not in those with metabolically healthy obesity (MHO; n = 48, p > 0.05). Circulating ANGPTL4, by contrast, was increased in all obese subgroups (all p < 0.001 vs. lean subjects). Vasodilator responses to both acetylcholine and sodium nitroprusside were reduced in the three obese subgroups vs. lean subjects (all p < 0.001), with greater impairment in the patients with T2D than in those with MHO and MUO (all p < 0.05). In the whole population, an inverse relationship (r = 0.27; p = 0.003) was observed between circulating ANGPTL4 and endothelium-dependent vasorelaxation. Circulating ANGPTL3 and ANGPTL4 undergo variable changes in obese patients with different metabolic phenotypes; changes in ANGPTL4 relate to endothelial dysfunction, making this protein a possible target for vascular prevention in these patients.

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Introduction: As adequate perfusion has turned out to be a key determinant of adipose tissue (AT) remodeling, interest has grown regarding possible pharmacological interventions to promote this process and hence prevent the metabolic abnormalities associated with obesity and aging. Clinical trials have shown that mirabegron improves insulin sensitivity and glucose homeostasis in obese humans via stimulation of β 3 -adrenoceptors. Ligands of these receptors have also emerged as endothelium-dependent vasodilators in disparate human vascular beds. Hypothesis: We hypothesized, therefore, that mirabegron might exert vasodilator effect in human AT arteries and tried to characterize the underlying mechanism(s). Methods: Small arteries (116-734 μm) isolated from visceral AT were studied ex vivo in a wire myograph. After vessels had been contracted, changes in vascular tone in response to mirabegron were determined under different experimental conditions. Results: Mirabegron elicited vasorelaxation in vessels contracted with endothelin-1 (P<0001), but not in those contracted with U46619 or high-K + (both P>0.05). Notably, mirabegron markedly blunted the contractile effect of the α 1 -adrenergic receptor agonist phenylephrine (P<0.001). Also, vessels with removed endothelium contracted with phenylephrine had preserved vasorelaxing response to mirabegron. The anti-contractile action of mirabegron on phenylephrine-induced vasoconstriction was not influenced by the presence of the selective β 3 -adrenoceptor blocker L-748,337 (P<0.05); lack of involvement of β 3 -adrenoceptors was further supported by absent vascular staining for them at immunohistochemistry. Similar to the observed effect of mirabegron, preincubation with the α 1 -adrenoceptor antagonist doxazosin abolished the contractile response to phenylephrine. Conclusions: Mirabegron induces endothelium-independent vasorelaxation in arteries from visceral adipose tissue, likely through antagonism of α 1 -adrenoceptors. This action suggests that mirabegron might effectively improve visceral AT perfusion, thereby favoring a healthy AT remodeling and preventing, in turn, some of the unwanted cardiometabolic consequences of obesity and aging.

Background: Obesity is linked with heightened cardiovascular risk, especially when accompanied by metabolic abnormalities. Lipocalin (LCN) 2 and retinol-binding protein (RBP) 4, two members of the lipocalin family, may be upregulated in insulin resistance and atherosclerosis. We analyzed whether changes in circulating LCN2 and RBP4 in obese individuals relate with impaired vasodilator reactivity, an early stage in atherosclerosis. Methods: Obese individuals ( n = 165), without ( n = 48) or with ( n = 117) metabolic abnormalities, and lean subjects ( n = 42) participated in this study. LCN2 and RBP4 were measured by Luminex assay. Endothelium-dependent and -independent vasodilation to acetylcholine and sodium nitroprusside, respectively, was assessed by strain-gauge plethysmography. Results: Circulating LCN2 was higher in obese than in lean subjects ( p < 0.001), whereas RBP4 was not different between the two groups ( p = 0.12). The vasodilator responses to both acetylcholine and nitroprusside were impaired in obese individuals ( p < 0.001 vs lean subjects), with no difference between those with metabolically healthy or unhealthy obesity ( p > 0.05). In the whole population, vasodilator responses to acetylcholine ( R = 0.23, p = 0.01) and nitroprusside ( R = 0.38, p < 0.001) had an inverse, linear relationship with circulating LCN2; no correlation, by contrast, was observed between circulating RBP4 and vasodilator reactivity (both p > 0.05). In a subgroup of obese patients with diabetes ( n = 20), treatment with metformin ( n = 10) or pioglitazone ( n = 10) did not modify circulating LCN2 and RBP4 or vascular reactivity (all p > 0.05). Conclusions: Circulating LCN2, but not RBP4, is higher in obese than in lean individuals. Interestingly, changes in LCN2 inversely relate to those in vasodilator function, thereby making this protein a potential biomarker for risk stratification in obesity.