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

Zhaohui Liao, Anuradha Chakrabarty, Ying Mu, Aritra Bhattacherjee, Martha Goestch, Catherine Leclair, Peter G. Smith

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Previous 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 angiotensin II receptor type 2 (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, whereas mast cells were unchanged. RAS proteins were increased because of 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, whereas 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 mechanonociceptor 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 AT2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.

Original languageEnglish (US)
JournalJournal of Pain
DOIs
StateAccepted/In press - Oct 21 2016

Fingerprint

Vulvodynia
Renin-Angiotensin System
Angiotensin II
Axons
Conditioned Culture Medium
Inflammation
Nociceptors
Hypersensitivity
T-Lymphocytes
Mast Cells
B-Lymphocytes
Macrophages
Angiotensin Type 2 Receptor
Chymases
Pain
Angiotensin I
Angiotensinogen
Sensory Receptor Cells
Neutralizing Antibodies
Renin

Keywords

  • Angiotensin II
  • Cell culture
  • Inflammation
  • Neural plasticity
  • Peripheral nociceptors
  • Quantitative histology
  • Vulvodynia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia. / Liao, Zhaohui; Chakrabarty, Anuradha; Mu, Ying; Bhattacherjee, Aritra; Goestch, Martha; Leclair, Catherine; Smith, Peter G.

In: Journal of Pain, 21.10.2016.

Research output: Contribution to journalArticle

Liao, Zhaohui ; Chakrabarty, Anuradha ; Mu, Ying ; Bhattacherjee, Aritra ; Goestch, Martha ; Leclair, Catherine ; Smith, Peter G. / A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia. In: Journal of Pain. 2016.
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AU - Mu, Ying

AU - Bhattacherjee, Aritra

AU - Goestch, Martha

AU - Leclair, Catherine

AU - Smith, Peter G.

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AB - Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Previous 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 angiotensin II receptor type 2 (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, whereas mast cells were unchanged. RAS proteins were increased because of 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, whereas 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 mechanonociceptor 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 AT2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.

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KW - Inflammation

KW - Neural plasticity

KW - Peripheral nociceptors

KW - Quantitative histology

KW - Vulvodynia

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