A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

Abstract

Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Prior experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on AT2 receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients’ nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages and B-cells, while mast cells were unchanged. RAS proteins were increased due to greater numbers of T-cells and B-cells expressing angiotensinogen, and increased renin-expressing T-cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, while those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechano-nociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain syndrome. Perspective: This study provides evidence that local inflammation leads to angiotensin II formation which acts on the angiotensin II receptor type 2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.

Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain

“…However, hindpaw Ang II injection led to local M⌽ infiltration in the skin without any influence on microglia/M⌽s in the DRG and spinal cord. Increased peripheral M⌽ infiltration and expression of renin-angiotensin system (RAS) components therein, such as angiotensinogen, renin, angiotensin-converting enzyme, and AT2R, have been shown in rodent models of CFA-induced inflammation and vestibulodynia (Chakrabarty et al, 2013(Chakrabarty et al, , 2018Liao et al, 2017). Furthermore, increased expression of RAS components, including AT2R, has been shown to accompany the differentiation of M⌽s from monocytes (Okamura et al, 1999).…”

“…A recent phase II clinical trial of a peripherally acting AT2R antagonist demonstrated successful alleviation of neuropathic pain associated with PHN (Rice et al, 2014). However, the underlying mechanism remains enigmatic, with a number of studies showing that the mechanism of action may involve AT2R antagonism directly on sensory neurons (for review, see and other studies finding no direct functional role of sensory neuron AT2R (Forte et al, 2016;Liao et al, 2017;Chakrabarty et al, 2018). We began with an unambiguous verification of the role of Ang II signaling in pain sensitization.…”

“…sensory neurons. This signaling axis is targeted by the AT2R antagonist PD123319, which dampens ROS/RNS production, representing a mechanism by which nociceptor excitation could be attenuated to provide relief from chronic pain conditions observed in experi-mental rodent models (Chakrabarty et al, 2013(Chakrabarty et al, , 2018Liao et al, 2017) and in humans (Rice et al, 2014).…”

Innervation Changes Induced by Inflammation in the Murine Vagina

“…Neurochemical characterization of nerve fibres in vaginal biopsies from women with vulvodynia is limited. Increased CGRP-containing nerve fibres (Bohm-Starke et al, 1999) and fibres expressing TRPV1 (Tympanidis et al, 2004) and TRPV4 (Liao et al, 2017) have been identified. TRPV1 receptors are activated by multiple mechanical and chemical stimuli and are mainly found in nociceptors, including many DRG neurons containing both SP and CGRP (Price and Flores, 2007).…”

Involvement of dopaminergic signaling in the cross talk between the renin-angiotensin system and inflammation

“…Ang(1-7) in turn may stimulate the Mas receptor (MasR), exerting anti-inflammatory and regenerative effects [8][9][10]. Importantly, in addition to the systemic RAS, several local RAS have been also identified in individual organs, where it plays a role not only in the homeostasis of blood pressure but also in the regulation of local immune response [11][12][13][14].…”