IN VITRO FUNCTIONAL INTERPLAY BETWEEN PERIVASCULAR ADIPOSE TISSUE AND FLAVONOIDS: CRITICAL ROLE OF BETA3 RECEPTOR AND SUPEROXIDE ANION

Flavonoids, a class of natural polyphenols abundantly present in our diet, have been shown to exert in vitro vasorelaxant activity. This was ascribed to a direct effect on the smooth muscle or factors released by the endothelium. Nowadays, perivascular adipose tissue (PVAT) is emerging as a fine regulator of blood vessel contractility. Therefore, it is conceivable to hypothesize that flavonoids vasoactivity may occur also through or is influenced, either positively or negatively, by PVATreleased factors. This hypothesis was assessed in vitro on rat aorta rings. Several flavonoids proved to display both antispasmodic and spasmolytic activity towards noradrenaline-induced contraction of rings deprived of PVAT (-PVAT). However, when PVAT was present (+PVAT), both activities of some flavonoids were lost and/or much decreased. In rings-PVAT, the superoxide donor pyrogallol mimicked the effect of PVAT, whereas in rings+PVAT the antioxidant mito-tempol restored both activities of the two most powerful flavonoids, namely apigenin and chrysin. The Rho-kinase inhibitor fasudil, or apigenin and chrysin concentration-dependently relaxed the vessel active tone induced by the Rho-kinase activator NaF; the presence of PVAT counteracted apigenin spasmolytic activity though only in the absence of mito-tempol. Similar results were obtained in rings pre-contracted with phenylephrine. Finally, when β3 receptors were blocked by SR59230A, the vasorelaxant activity of both flavonoids was no more affected by PVAT. These findings are coherent with the hypothesis that both noradrenaline and apigenin activated adipocyte β3 receptors with the ensuing release of mitochondrial superoxide anion, which once diffused toward myocytes counteracted flavonoid vasorelaxant activity, thus underlining the control of adipocytes upon the vascular tone. This phenomenon might limit the beneficial health effects of this class of natural compounds in patients affected by either obesity and/or other pathological conditions characterized by sympathetic nerve overactivity.