title: A Toll-Like Receptor 1/2 Agonist Augments Contractility in Rat Corpus Cavernosum.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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 Pam3 CSK4 (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.
  
  
  METHODS
  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.
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Inger
authors.initials: I
authors.lastname: Stallmann-Jorgensen
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Safia
authors.initials: S
authors.lastname: Ogbi
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Theodora
authors.initials: T
authors.lastname: Szasz
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D007172:Erectile Dysfunction / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology*; D010413:Penis / Q000098:blood supply / Q000294:innervation / Q000473:pathology*; D051381:Rats; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D009569:Nitric Oxide; D054460:rho-Associated Kinases
keywords: Corpus Cavernosum; Erectile Function; Myography; Nitric Oxide; Rho-Kinase; Toll-Like Receptor 1; Toll-Like Receptor 2; Vascular Dysfunction