RhoA/Rho-kinase in erectile tissue: mechanisms of disease and therapeutic insights

Abstract

Penile erection is a complicated event involving the regulation of corpus cavernosal smooth muscle tone. Recently, the small monomeric G-protein RhoA and its downstream effector Rho-kinase have been proposed to be important players for mediating vasoconstriction in the penis. RhoA/Rho-kinase increases MLC (myosin light chain) phosphorylation through inhibition of MLCP (MLC phosphatase) thereby increasing Ca2+ sensitivity. This review will outline the RhoA/Rho-kinase signalling pathway, including the upstream regulators, guanine nucleotide exchange factors, GDP dissociation inhibitors and GTPase-activating proteins. We also summarize the current knowledge about the physiological roles of RhoA/Rho-kinase in both male and female erectile tissues and its aberrations contributing to erectile dysfunction in several disease states. Understanding the RhoA/Rho-kinase signalling pathway in the regulation of erection is important for the development of therapeutic interventions for erectile dysfunction.

Losartan Preserves Erectile Function by Suppression of Apoptosis and Fibrosis of Corpus Cavernosum and Corporal Veno-Occlusive Dysfunction in Diabetic Rats

“…These results may provide clues for a better understanding of the molecular mechanisms of Ang II in apoptosis and fibrosis in the corpus cavernosum and severe CVOD, and of the critical role of Ang II in functional and morphological modification in the cavernous tissue of diabetic rats through Smad- and non-Smad-related signaling pathways. Furthermore, considering the fact that Rho/ROCK plays a pivotal role in diabetic ED by inducing cavernosal fibrosis [45] and increasing smooth muscle tone in the corpus cavernosum [46], Rho/ROCK may also be involved in mediating Ang II-induced diabetes-associated ED. Further studies are needed to clarify this relationship and whether combined inhibition of both signaling pathways could improve diabetes-induced cavernosal fibrosis and CVOD.…”

Emerging and Novel Therapeutic Approaches in the Treatment of Male Erectile Dysfunction

“…Chitaley et al [8] reported that Rho-kinase antagonism stimulated rat penile erection independently of nitric oxide (NO) and showed potential alternative therapeutic options to treat ED. In fact, recently published literature has suggested that elevated RhoA/Rhokinase activity contributes to the pathogenesis of ED in conditions such as diabetes, aging, and hypogonadism [9]. Vignozzi et al [10] found that overexpression of RhoA/ Rho-kinase signalling contributed to diabetes-related ED and that treating hypogonadism-associated diabetes could improve the erectile function by normalizing the RhoA/Rhokinase pathway upregulation.…”

Animal models of erectile dysfunction

“…Within this perception, pharmacological blockage of AT 1 receptor/Ang-II actions through the use of ACE inhibitors and AT 1 receptor blockers, along with the use of oxidase inhibitors, anti fibrotic and Rho-Kinase inhibitors, have been reported to have positive effects on erections (Decaluwe, Pauwels, Verpoest, & Van de Voorde, 2011;Doumas & Douma, 2006;Fraga-Silva, Montecucco, Mach, Santos, & Stergiopulos, 2013;Jin & Burnett, 2006;Jin, Lagoda, Leite, Webb, & Burnett, 2008).…”