A Toll-Like Receptor 1/2 Agonist Augments Contractility in Rat Corpus Cavernosum

Inger Stallmann-Jorgensen, Safia Ogbi, Theodora Szasz, R Clinton Webb

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Introduction: Activation of the innate immune Toll-like receptor 2 (TLR2) initiates inflammation and has been implicated in vascular dysfunction. Increased contraction and decreased relaxation responses in the penile vasculature lead to erectile dysfunction, a condition associated with inflammation. However, whether TLR2 activation plays a role in penile vascular function has not been established. Aim: We hypothesized that activation of the TLR 1/2 heterodimer (TLR1/2) augments contractile and impairs relaxation responses of corpus cavernosum and that these perturbations of vascular function are mediated by low nitric oxide (NO) availability and enhanced activity of the RhoA/Rho-kinase pathway. Methods: Contraction and relaxation responses were measured in rat cavernosal strips using a myograph after incubation with a TLR1/2-activating ligand Pam<inf>3</inf>CSK<inf>4</inf> (Pam3), the TLR1/2 inhibitor CuCPT 22 (CuCPT), and inhibitors of NO synthase (LNAME) and Rho-kinase (Y27632). TLR2 protein expression was assessed by immunohistochemistry. Main Outcome Measures: Cumulative concentration response curves, sensitivity (pEC50), and maximal response (E<inf>max</inf>) of cavernosal strips to vasodilatory and vasocontractile agonists were compared between treatments. Results: Pam3-treated cavernosal strips exhibited greater pEC50 and higher E<inf>max</inf> to phenylephrine (PE) than control tissues. Inhibition of NO synthase increased E<inf>max</inf> to PE in Pam3-treated cavernosal strips. Pam3 treatment reduced relaxation to Y27632 compared with control tissues. Inhibition of TLR1/2 activation with CuCPT returned the augmented contraction to PE and the decreased relaxation to Y27632 of Pam3-treated cavernosal strips to control values. Conclusions: The TLR1/2 heterodimer mediates augmented contraction and reduced relaxation in rat cavernosal strips. Thus, TLR1/2 activation antagonizes vascular responses crucial for normal erectile function and implicates immune activation in vasculogenic erectile dysfunction. Immune signaling via TLR2 may offer novel targets for treating inflammation-mediated vascular dysfunction in the penis.

Original languageEnglish (US)
Pages (from-to)1722-1731
Number of pages10
JournalJournal of Sexual Medicine
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

Toll-Like Receptor 1
Toll-Like Receptor 2
Blood Vessels
Phenylephrine
rho-Associated Kinases
Erectile Dysfunction
Inflammation
Nitric Oxide Synthase
Penis
Nitric Oxide
Immunohistochemistry
Outcome Assessment (Health Care)
Ligands
Therapeutics
Y 27632
Proteins

Keywords

  • Corpus Cavernosum
  • Erectile Function
  • Myography
  • Nitric Oxide
  • Rho-Kinase
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Vascular Dysfunction

ASJC Scopus subject areas

  • Urology
  • Obstetrics and Gynecology
  • Reproductive Medicine

Cite this

A Toll-Like Receptor 1/2 Agonist Augments Contractility in Rat Corpus Cavernosum. / Stallmann-Jorgensen, Inger; Ogbi, Safia; Szasz, Theodora; Webb, R Clinton.

In: Journal of Sexual Medicine, Vol. 12, No. 8, 01.08.2015, p. 1722-1731.

Research output: Contribution to journalArticle

Stallmann-Jorgensen, Inger ; Ogbi, Safia ; Szasz, Theodora ; Webb, R Clinton. / A Toll-Like Receptor 1/2 Agonist Augments Contractility in Rat Corpus Cavernosum. In: Journal of Sexual Medicine. 2015 ; Vol. 12, No. 8. pp. 1722-1731.
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abstract = "Introduction: Activation of the innate immune Toll-like receptor 2 (TLR2) initiates inflammation and has been implicated in vascular dysfunction. Increased contraction and decreased relaxation responses in the penile vasculature lead to erectile dysfunction, a condition associated with inflammation. However, whether TLR2 activation plays a role in penile vascular function has not been established. Aim: We hypothesized that activation of the TLR 1/2 heterodimer (TLR1/2) augments contractile and impairs relaxation responses of corpus cavernosum and that these perturbations of vascular function are mediated by low nitric oxide (NO) availability and enhanced activity of the RhoA/Rho-kinase pathway. Methods: Contraction and relaxation responses were measured in rat cavernosal strips using a myograph after incubation with a TLR1/2-activating ligand Pam3CSK4 (Pam3), the TLR1/2 inhibitor CuCPT 22 (CuCPT), and inhibitors of NO synthase (LNAME) and Rho-kinase (Y27632). TLR2 protein expression was assessed by immunohistochemistry. Main Outcome Measures: Cumulative concentration response curves, sensitivity (pEC50), and maximal response (Emax) of cavernosal strips to vasodilatory and vasocontractile agonists were compared between treatments. Results: Pam3-treated cavernosal strips exhibited greater pEC50 and higher Emax to phenylephrine (PE) than control tissues. Inhibition of NO synthase increased Emax to PE in Pam3-treated cavernosal strips. Pam3 treatment reduced relaxation to Y27632 compared with control tissues. Inhibition of TLR1/2 activation with CuCPT returned the augmented contraction to PE and the decreased relaxation to Y27632 of Pam3-treated cavernosal strips to control values. Conclusions: The TLR1/2 heterodimer mediates augmented contraction and reduced relaxation in rat cavernosal strips. Thus, TLR1/2 activation antagonizes vascular responses crucial for normal erectile function and implicates immune activation in vasculogenic erectile dysfunction. Immune signaling via TLR2 may offer novel targets for treating inflammation-mediated vascular dysfunction in the penis.",
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T1 - A Toll-Like Receptor 1/2 Agonist Augments Contractility in Rat Corpus Cavernosum

AU - Stallmann-Jorgensen, Inger

AU - Ogbi, Safia

AU - Szasz, Theodora

AU - Webb, R Clinton

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Introduction: Activation of the innate immune Toll-like receptor 2 (TLR2) initiates inflammation and has been implicated in vascular dysfunction. Increased contraction and decreased relaxation responses in the penile vasculature lead to erectile dysfunction, a condition associated with inflammation. However, whether TLR2 activation plays a role in penile vascular function has not been established. Aim: We hypothesized that activation of the TLR 1/2 heterodimer (TLR1/2) augments contractile and impairs relaxation responses of corpus cavernosum and that these perturbations of vascular function are mediated by low nitric oxide (NO) availability and enhanced activity of the RhoA/Rho-kinase pathway. Methods: Contraction and relaxation responses were measured in rat cavernosal strips using a myograph after incubation with a TLR1/2-activating ligand Pam3CSK4 (Pam3), the TLR1/2 inhibitor CuCPT 22 (CuCPT), and inhibitors of NO synthase (LNAME) and Rho-kinase (Y27632). TLR2 protein expression was assessed by immunohistochemistry. Main Outcome Measures: Cumulative concentration response curves, sensitivity (pEC50), and maximal response (Emax) of cavernosal strips to vasodilatory and vasocontractile agonists were compared between treatments. Results: Pam3-treated cavernosal strips exhibited greater pEC50 and higher Emax to phenylephrine (PE) than control tissues. Inhibition of NO synthase increased Emax to PE in Pam3-treated cavernosal strips. Pam3 treatment reduced relaxation to Y27632 compared with control tissues. Inhibition of TLR1/2 activation with CuCPT returned the augmented contraction to PE and the decreased relaxation to Y27632 of Pam3-treated cavernosal strips to control values. Conclusions: The TLR1/2 heterodimer mediates augmented contraction and reduced relaxation in rat cavernosal strips. Thus, TLR1/2 activation antagonizes vascular responses crucial for normal erectile function and implicates immune activation in vasculogenic erectile dysfunction. Immune signaling via TLR2 may offer novel targets for treating inflammation-mediated vascular dysfunction in the penis.

AB - Introduction: Activation of the innate immune Toll-like receptor 2 (TLR2) initiates inflammation and has been implicated in vascular dysfunction. Increased contraction and decreased relaxation responses in the penile vasculature lead to erectile dysfunction, a condition associated with inflammation. However, whether TLR2 activation plays a role in penile vascular function has not been established. Aim: We hypothesized that activation of the TLR 1/2 heterodimer (TLR1/2) augments contractile and impairs relaxation responses of corpus cavernosum and that these perturbations of vascular function are mediated by low nitric oxide (NO) availability and enhanced activity of the RhoA/Rho-kinase pathway. Methods: Contraction and relaxation responses were measured in rat cavernosal strips using a myograph after incubation with a TLR1/2-activating ligand Pam3CSK4 (Pam3), the TLR1/2 inhibitor CuCPT 22 (CuCPT), and inhibitors of NO synthase (LNAME) and Rho-kinase (Y27632). TLR2 protein expression was assessed by immunohistochemistry. Main Outcome Measures: Cumulative concentration response curves, sensitivity (pEC50), and maximal response (Emax) of cavernosal strips to vasodilatory and vasocontractile agonists were compared between treatments. Results: Pam3-treated cavernosal strips exhibited greater pEC50 and higher Emax to phenylephrine (PE) than control tissues. Inhibition of NO synthase increased Emax to PE in Pam3-treated cavernosal strips. Pam3 treatment reduced relaxation to Y27632 compared with control tissues. Inhibition of TLR1/2 activation with CuCPT returned the augmented contraction to PE and the decreased relaxation to Y27632 of Pam3-treated cavernosal strips to control values. Conclusions: The TLR1/2 heterodimer mediates augmented contraction and reduced relaxation in rat cavernosal strips. Thus, TLR1/2 activation antagonizes vascular responses crucial for normal erectile function and implicates immune activation in vasculogenic erectile dysfunction. Immune signaling via TLR2 may offer novel targets for treating inflammation-mediated vascular dysfunction in the penis.

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KW - Toll-Like Receptor 2

KW - Vascular Dysfunction

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