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

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 (E_max) of cavernosal strips to vasodilatory and vasocontractile agonists were compared between treatments. Results: Pam3-treated cavernosal strips exhibited greater pEC50 and higher E_max to phenylephrine (PE) than control tissues. Inhibition of NO synthase increased E_max 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.