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Neurovascular Effects of Perivascular Adipose Tissue

Regulation of Sympathetic-Sensory Communication

Pulgar, Victor M. PhD*,†

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Journal of Cardiovascular Pharmacology: January 2020 - Volume 75 - Issue 1 - p 18-20
doi: 10.1097/FJC.0000000000000776
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This editorial refers to “Perivascular adipose tissue modulation of neurogenic vasorelaxation of rat mesenteric arteries,” by Chang et al pp.

Different types of adipose tissues, namely white adipose tissue (WAT), beige, and brown adipose tissue (BAT), display different structural and functional characteristics. High mitochondria content and a role in thermogenesis are among the main characteristics of BAT, whereas WAT is characterized by low mitochondria content and a more predominant endocrine role.1 Several evidences have shown that depending on its anatomical location, the adipose tissue surrounding the vasculature, perivascular adipose tissue (PVAT), shares some structural and functional characteristics with BAT or WAT. As an example, although thoracic aorta PVAT resembles BAT, abdominal aorta PVAT shares similarities with WAT. In particular, the adipose tissue surrounding the mesenteric artery has been shown to have WAT-like characteristics.1

Although initially absent from most vascular studies, PVAT is being recognized as an important mediator of vascular function and dysfunction. PVAT releases a number of vasoactive substances with vasodilatory and vasoconstrictor properties.2 Some of those substances include adiponectin, H2S, glucagon-like peptide 1, and a number of pro-inflammatory cytokines also called adipokines. Importantly, the PVAT-derived lipid methyl palmitate or palmitate methyl ester is described as a direct vasodilator3 and as a regulator of nicotine-dependent neuronal transmission.4

It has been long recognized that arteries, in particular small resistance arteries such as those in the mesenteric arterial bed, are highly innervated and under autonomic control. Several immunolocalization studies showed that this innervation included sympathetic nerves, C and Aδ sensory fibers, and in a lower degree, parasympathetic nerves.5 The sensory fibers release substance P and calcitonin gene-related peptide (CGRP), a 37-aminoacid vasodilator peptide with potent endothelial-dependent and -independent vascular effects.6 In some instances, these nerve fibers colocalize as in the rat mesenteric artery where adrenergic nerves and CGRP-containing nerves exist in close proximity.7 The release of neurotransmitters from adrenergic nerves may inhibit CGRP release from sensory nerves, and conversely, blockade of CGRPergic nerve function may increase adrenergic-mediated vasoconstriction. This reciprocal functional regulation may occur in part via axoaxonal interactions in the perivascular environment.5,8 Because adrenergic neurotransmitters are maintained in an acidic environment in storage vesicles, upon activation, terminal nerves release their vesicle contents, which include neurotransmitters and protons. Consequently, acidosis seems concomitant to neurotransmitter release in perivascular nerves, and it has been suggested that protons are the actual mediators of axoaxonal sympathetic-sensory communications8; thus, protons coreleased with catecholamines upon sympathetic activation would activate transient receptor potential vanilloid 1 (TRPV1) channels in sensory fibers to release CGRP and produce vasodilatation5 (Fig. 1).

Signals originating from adrenergic fibers (tyrosine hydroxylase positive, TH+, yellow) and from sensory nerve fibers (CGRP+, yellow) functionally interact in a bidirectional way (dashed arrow) on the vascular wall (red). Upon activation, adrenergic fibers release their cargo including protons (H+) which will activate transient receptor potential vanilloid 1 (TRVP1) channels in sensory nerves releasing CGRP and producing vasodilatation. PVAT-derived methyl palmitate (palmitate methyl ester, PAME) interferes with the nicotinic receptor–dependent release of catecholamines and protons (H+), thus attenuating the acidosis-mediated component of the sympathetic-mediated vasodilatory response.

In the current issue of J Cardiovasc Pharmacol, Chang et al.9 have provided evidence that PVAT-derived mediators regulate the interactions between sympathetic and sensory perivascular nerves in small-resistance arteries. By studying neurogenic relaxation in rat mesenteric artery, the authors showed that in arteries with active tone nicotine induced an endothelium-independent vasorelaxation only in the absence of PVAT. By contrast, the vasodilatory response induced by transmural nerve stimulation was independent of PVAT. Furthermore, this vasodilatation was dependent on catecholamines and blocked by the inhibition of sensory nerve conduction by treatment with the CGRP depletory capsaicin. Chang et al further show that H2S or leptin is not involved in this response; however, in the presence of methyl palmitate, this neurogenic vasodilatation is inhibited. The authors proposed that methyl palmitate blocks nicotinic receptors on the sympathetic neurons, thus reducing the release of catecholamines and protons and attenuating subsequent axoaxonal interactions. Lending additional support to the axoaxonal hypothesis, Chang et al. also show that a CGRP receptor antagonist blocked acidosis-dependent vasodilatation in the mesenteric artery.

These results are important because they add to the knowledge of the growing potential for vascular regulatory control by the adipocyte in maintaining homeostasis of the mesenteric circulation. In particular, the data presented highlight the effects of PVAT-derived mediators on the functional interactions between sympathetic and sensory nerves in the vasculature.

Recently, the importance of beta adrenergic receptors in mesenteric artery dilatation has been investigated in vivo,10 and these studies showed that β1 adrenergic receptors are the main receptors responsible for small resistance vasodilation. In contrast with the results in Chang et al,9 CGRP-dependent dilatation was negligible in vivo. Because axoaxonal communication involves the release of adrenergic agonists, new studies on the potential effects of PVAT-derived mediators such as methyl palmitate on adrenergic-mediated responses in general and particularly adrenergic-mediated vasodilatation are expected.

An example of sensory-sympathetic axoaxonal communication is the enhancement of sympathetic nerve‐mediated vasoconstriction after inhibition of CGRP release from sensory nerves by capsaicin. In a model of experimental obesity, this enhancement is diminished in obese animals,11 suggesting a potential effect of obesity in lowering the sensitivity of axoaxonal interactions. An increased attenuation of CGRP-mediated vasodilation by PVAT-derived methyl palmitate may be related to this effect and indirectly contribute to the anticontractile effects of PVAT by modulating autonomic nerve responses.

Levels of metabolites important in cardiovascular diseases differ between human subjects classified as metabolic healthy obese and metabolic abnormal obese. Interestingly, the metabolic abnormal obese group displays greater risks of cardiovascular diseases and higher levels of methyl palmitate, among others metabolites.12 Because several reports have shown that the anticontractile effects of PVAT are lost in obesity, it is conceivable that an enhanced inhibition of CGRP-mediated vasodilatation by increased levels of methyl palmitate is also playing a role in obesity-induced vascular dysfunction.

Abundant literature shows now the autocrine/paracrine/endocrine functions of PVAT, in line with the important endocrine functions observed in WAT.1 One area of great interest will be the identification of mechanistic pathways linking autonomic control of vascular tone and the adipocyte. The work by Chang et al in this issue suggests that in addition to direct vascular regulation by PVAT-derived methyl palmitate, this lipid may mediate PVAT-derived control of axoaxonal communication in the small resistance vasculature. Whether this applies to additional PVAT-derived lipid mediators and the potential effects of this phenomenon on the progression of cardiovascular disease in obesity warrants further investigation.


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