Adiponectin at Physiologically Relevant Concentrations Enhances the Vasorelaxative Effect of Acetylcholine via Cav-1/AdipoR-1 Signaling

Abstract

Clinical studies have identified hypoadiponectinemia as an independent hypertension risk factor. It is known that adiponectin (APN) can directly cause vasodilation, but the doses required exceed physiologic levels several fold. In the current study, we determine the effect of physiologically relevant APN concentrations upon vascular tone, and investigate the mechanism(s) responsible. Physiologic APN concentrations alone induced no significant vasorelaxation. Interestingly, pretreatment of wild type mouse aortae with physiologic APN levels significantly enhanced acetylcholine (ACh)-induced vasorelaxation (P<0.01), an endothelium-dependent and nitric oxide (NO)-mediated process. Knockout of adiponectin receptor 1 (AdipoR1) or caveolin-1 (Cav-1, a cell signaling facilitating molecule), but not adiponectin receptor 2 (AdipoR2) abolished APN-enhanced ACh-induced vasorelaxation. Immunoblot assay revealed APN promoted the AdipoR1/Cav1 signaling complex in human endothelial cells. Treatment of HUVECs with physiologic APN concentrations caused significant eNOS phosphorylation and nitric oxide (NO) production (P<0.01), an effect abolished in knockdown of either AdipoR1 or Cav-1. Taken together, these data demonstrate for the first time physiologic APN levels enhance the vasorelaxative response to ACh by inducing NO production through AdipoR1/Cav-1 mediated signaling. In physiologic conditions, APN plays an important function of maintaining vascular tone.

Lack of direct effect of adiponectin on vascular smooth muscle cell BKCa channels or Ca2+ signaling in the regulation of small artery pressure-induced constriction

“…Furthermore, and in contrast to the earlier reports, a recent study has been unable to reproduce the vasodilation of preconstricted mouse aorta to adiponectin, even at higher doses (up to 15  μ g/mL) (Du et al. 2016), although in this study adiponectin did augment the vasodilation to acetylcholine. Perhaps consistent with this, Lynch et al.…”

“…Furthermore, a recent study has been unable to replicate any vasodilation to exogenous adiponectin of wire mounted rat aorta (even at higher doses) despite using identical protocols (Du et al. 2016) although adiponectin did augment the vasodilation to acetylcholine (Du et al. 2016).…”

“…2016) although adiponectin did augment the vasodilation to acetylcholine (Du et al. 2016). An additional consideration is that whilst we saw a small vasodilation to adiponectin, this effect was not sustained.…”

“…2013; Du et al. 2016). Although it is difficult to compare results using different experimental approaches on arteries of differing diameters, the vasodilation of pressure constricted arteries to adiponectin was similar to that seen by Lynch et al.…”

“…when no vasodilation of wire‐mounted preconstricted arteries to adiponectin was seen even at a dose of 15  μ g/mL (Du et al. 2016). The experimental approach with a single dose of adiponectin also replicates in vivo conditions.…”