Abstract
Background and PurposeIn response to noradrenaline, healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arterial tissue. Organ bath solution transfer experiments have demonstrated the release of PVAT‐derived relaxing factors that mediate this function. The present studies were designed to investigate the mechanism responsible for the noradrenaline‐induced PVAT anticontractile effect.Experimental Approach In vitro rat small arterial contractile function was assessed using wire myography in the presence and absence of PVAT and the effects of sympathomimetic stimulation on the PVAT environment explored using Western blotting and assays of organ bath buffer.Key ResultsPVAT elicited an anticontractile effect in response to noradrenaline but not phenylephrine stimulation. In arteries surrounded by intact PVAT, the β3‐adrenoceptor agonist, CL‐316243, reduced the vasoconstrictor effect of phenylephrine but not noradrenaline. Kv7 channel inhibition using XE 991 reversed the noradrenaline‐induced anticontractile effect in exogenously applied PVAT studies. Adrenergic stimulation of PVAT with noradrenaline and CL‐316243, but not phenylephrine, was associated with increased adipocyte‐derived NO production, and the contractile response to noradrenaline was augmented following incubation of exogenous PVAT with L‐NMMA. PVAT from eNOS−/− mice had no anticontractile effect. Assays of adipocyte cAMP demonstrated an increase with noradrenaline stimulation implicating Gαs signalling in this process.Conclusions and ImplicationsWe have shown that adipocyte‐located β3‐adrenoceptor stimulation leads to activation of Gαs signalling pathways with increased cAMP and the release of adipocyte‐derived NO. This process is dependent upon Kv7 channel function. We conclude that adipocyte‐derived NO plays a central role in anticontractile activity when rodent PVAT is stimulated by noradrenaline.
Highlights
Perivascular adipose tissue (PVAT) surrounds virtually all blood vessels and exerts an anticontractile effect in response to various vasoconstrictor agonists (Gao et al, 2007; Greenstein et al, 2009)
The vasoconstrictor response to norepinephrine was reduced in vessels lacking perivascular adipose tissue (PVAT) with exogenous PVAT suspended in the bath (Figure 1A) suggesting that the anticontractile effect was due to secretion of a soluble factor
Adipocyte located β3-adrenergic activation produces a PVAT-derived anticontractile effect via Gαs signaling Western blot analysis indicated the presence of β3-adrenoceptors within the PVAT of rat mesenteric arteries (Figure 2A), we investigated the contribution of β3adrenergic signaling to the anticontractile effect
Summary
Perivascular adipose tissue (PVAT) surrounds virtually all blood vessels and exerts an anticontractile effect in response to various vasoconstrictor agonists (Gao et al, 2007; Greenstein et al, 2009). The mechanisms by which PVAT exerts this effect are the subject of intense investigations and what is clear already from organ bath studies is that adipocytes release transferable relaxing factor(s) (Lohn et al, 2002; Greenstein et al, 2009). Pharmacological investigations have led to the identification of several potassium channel candidates including Kv7 (Fésüs et al, 2007; Schleifenbaum et al, 2010) and BKCa (Gao et al, 2005; Lynch et al, 2013), which appear to undergo differential activation depending on the vascular bed and species investigated These studies indicate the emerging importance of PVAT, which appears to exert its anticontractile effect through a variety of complex pathways that may be activated in parallel in response to different agonists. Assays of adipocyte cAMP demonstrated an increase with norepinephrine stimulation implicating Gαs signalling in this process
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