β3-adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived nitric oxide and vascular relaxation in small arteries

Bussey, CE; Withers, SB; Saxton, SN; Bodagh, N; Aldous, RG; Heagerty, AM

Abstract

BACKGROUND AND PURPOSE
In response to norepinephrine 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 norepinephrine-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 RESULTS
PVAT elicited an anticontractile effect in response to norepinephrine but not phenylephrine stimulation. In arteries surrounded by intact PVAT, the β3-adrenoceptor agonist, CL-316,243 reduced the vasoconstrictor effect of phenylephrine but not norepinephrine. Kv7 channel inhibition using XE 991 reversed the norepinephrine-induced anticontractile effect in exogenously applied PVAT studies. Adrenergic stimulation of PVAT with norepinephrine and CL-316,243, but not phenylephrine was associated with increased adipocyte-derived nitric oxide production and the contractile response to norepinephrine 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 norepinephrine stimulation implicating Gαs signalling in this process.
CONCLUSIONS AND IMPLICATIONS
We have shown that adipocyte-located β3-adrenoceptor stimulation leads to activation of Gαs signaling pathways with increased cAMP and the release of adipocyte-derived nitric oxide. This process is dependent upon Kv7 channel function. We conclude that adipocyte-derived nitric oxide plays a central role in anticontractile activity when rodent PVAT is stimulated by norepinephrine.

Citation

Bussey, C., Withers, S., Saxton, S., Bodagh, N., Aldous, R., & Heagerty, A. (2018). β3-adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived nitric oxide and vascular relaxation in small arteries. British Journal of Pharmacology, 175(18), 2685-3698. https://doi.org/10.1111/bph.14433

• Journal Article Type: Article
• Acceptance Date: Jun 19, 2018
• Online Publication Date: Jul 6, 2018
• Publication Date: Jul 6, 2018
• Deposit Date: Sep 28, 2018
• Publicly Available Date: Jul 6, 2019
• Journal: British Journal of Pharmacology
• Print ISSN: 0007-1188
• Publisher: Wiley
• Volume: 175
• Issue: 18
• Pages: 2685-3698
• DOI: https://doi.org/10.1111/bph.14433
• Publisher URL: https://doi.org/10.1111/bph.14433
• Related Public URLs: https://bpspubs.onlinelibrary.wiley.com/journal/14765381