Role of Sympathetic Nerves and Adipocyte Catecholamine Uptake in the Vasorelaxant Function of Perivascular Adipose Tissue

Abstract

Objective— Healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on resistance arteries which is vital in regulating arterial tone. Activation of β 3 -adrenoceptors by sympathetic nerve–derived NA (noradrenaline) may be implicated in this effect and may stimulate the release of the vasodilator adiponectin from adipocytes. Understanding the mechanisms responsible is vital for determining how PVAT may modify vascular resistance in vivo. Approach and Results— Electrical field stimulation profiles of healthy C57BL/6J mouse mesenteric resistance arteries were characterized using wire myography. During electrical field stimulation, PVAT elicits a reproducible anticontractile effect, which is endothelium independent. To demonstrate the release of an anticontractile factor, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT-denuded vessel. Post-transfer contractility was significantly reduced confirming that stimulated PVAT releases a transferable anticontractile factor. Sympathetic denervation of PVAT using tetrodotoxin or 6-hydroxydopamine completely abolished the anticontractile effect. β 3 -adrenoceptor antagonist SR59203A reduced the anticontractile effect, although the PVAT remained overall anticontractile. When the antagonist was used in combination with an OCT3 (organic cation transporter 3) inhibitor, corticosterone, the anticontractile effect was completely abolished. Application of an adiponectin receptor-1 blocking peptide significantly reduced the anticontractile effect in +PVAT arteries. When used in combination with the β 3 -adrenoceptor antagonist, there was no further reduction. In adiponectin knockout mice, the anticontractile effect is absent. Conclusions— The roles of PVAT are 2-fold. First, sympathetic stimulation in PVAT triggers the release of adiponectin via β 3 -adrenoceptor activation. Second, PVAT acts as a reservoir for NA, preventing it from reaching the vessel and causing contraction.

Perivascular Adipose Tissue as a Target for Antioxidant Therapy for Cardiovascular Complications

“…Furthermore, sympathetic stimulation can trigger the release of adiponectin via β3-adrenoceptor activation in PVAT [39]. Moreover, PVAT can also prevent noradrenaline-induced vasocontraction, by acting as a reservoir of noradrenaline and preventing it from reaching the vessel wall [39]. These studies suggest that PVAT possesses various underdetermined mechanisms, in addition to releasing vasoactive factors, to regulate the vascular function.…”

“…In rat mesenteric arteries, the inhibition of MAO and SSAO, or the inhibition of norepinephrine transporter (NET) with nisoxetine reduced PVAT's anticontractile effect in response to NE-induced vasocontraction. Furthermore, sympathetic stimulation can trigger the release of adiponectin via β3-adrenoceptor activation in PVAT [39]. Moreover, PVAT can also prevent noradrenaline-induced vasocontraction, by acting as a reservoir of noradrenaline and preventing it from reaching the vessel wall [39].…”

Influence of Age on Anticontractile Effect of Perivascular Adipose Tissue in Normotensive and Hypertensive Rats

“…In SHR, these substances are produced in increased amount [26, 27]; therefore, they could be even more abundantly released from PVAT during TES, and they might seemingly eliminate the anticontractile effect of PVAT. Moreover, an important role might play the increased density of sympathetic innervation in arterial wall, which is characteristic of SHR; in arteries from these rats, the multiplied sympathetic nerves may extend into PVAT which means that PVAT itself could be a source of endogenous noradrenaline released during TES [28]. All the mentioned factors can partially be causing that in SHR mesenteric arteries, the intact PVAT does not manifest anticontractile effect on neurogenic contractions, because during TES, besides inhibitory PVAT-derived factors, substances producing contraction might also be released from PVAT.…”

Emerging Roles of Sympathetic Nerves and Inflammation in Perivascular Adipose Tissue

“…The tight packing of adipocytes has made it difficult to visualise direct contact between nerves and adipocytes, and histological studies are conflicting. Studies using markers for sympathetic nerves agree that they are present in both BAT and WAT depots, including visceral, subcutaneous and perivascular depots [19, 66–68]. Whilst most tissues receive dual autonomic innervation, i.e.…”

“…In obesity, where autonomic dysfunction is known to occur, PVAT becomes inflamed and its secretory profile becomes dysfunctional [11, 18]. Loss of PVAT function may contribute to the vascular complications associated with obesity such as hypertension and type-II diabetes [19–22].…”