Endothelial Nitric Oxide Synthase Keeps Erection Regulatory Function Balance in the Penis

Abstract

Objectives: We sought to evaluate the regulatory influence of endothelial nitric oxide (NO) on the basal functional states of the NO and RhoA/Rho-kinase signaling pathways in the penis employing endothelial NO synthase (eNOS) mutant mice and eNOS gene transfer technology.Methods: Four groups of mice were utilized: 1) wild type (WT), 2) eNOS gene deleted (eNOS −/−), 3) eNOS and neuronal NOS gene deleted (dNOS −/−), and 4) eNOS −/− mutant mice transfected intracavernosally with eNOS. Cyclic guanosine monophosphate (cGMP) concentration, protein kinase G (PKG) activity, activated RhoA, and Rho-kinase activity were determined in penes of WT and both mutant mouse groups. Constitutive NOS and PKG activities, RhoA, Rho-kinase-α and-β isoforms, and phosphorylated myosin light chain phosphatase target subunit (p-MYPT-1) expressions as well as Rho-kinase activity were determined in penes of eNOS−/− mice after eNOS gene transfer. Results:When compared with results in the WT penis, eNOS−/− and dNOS−/− mutant mouse penes had significant reductions in NOS activity, cGMP concentration, PKG activity, Rho-kinase activity and p-MYPT-1 expression (p<0.05) with no significant changes in activated RhoA or in RhoA and Rho-kinase-α and-β protein expressions. After eNOS gene transfer to penes of eNOS−/ − mice, Rho-kinase-β and p-MYPT-1 expressions and total Rho-kinase activity were significantly increased from baseline levels (p<0.05). Conclusions:These data suggest that endothelial NO serves a role in the penis as a regulator of the basal signaling functions of the NO and RhoA/Rho-kinase erection mediatory pathways. These data offer new insight into the homeostasis of erection regulatory biology.

Arginase Inhibition by Ethylacetate Extract ofCaesalpinia sappanLignum Contributes to Activation of Endothelial Nitric Oxide Synthase

“…Furthermore, reciprocal regulation of NOS by arginase has been demonstrated in cells and organs in which NO is an important signaling molecule, including the endothelium, cardiac myocytes, penis, airway, skin, and inflammatory cells [4][5][6]10,16,[29][30][31]. It was demonstrated that arginase II activity is upregulated in atherosclerosis-prone mice and is associated with impaired endothelial NO production, endothelial dysfunction, vascular stiffness, and ultimately, aortic plaque development.…”

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

“…4) in which nNOS initiates the erectile response, which is then maintained and increased by eNOS activity (the latter being activated by shear stress) (Hurt et al, 2002(Hurt et al, , 2006Musicki and Burnett, 2006;Bivalacqua et al, 2007b;Musicki et al, 2009). eNOS has an indispensable role in the erectile response, and its activity and endothelial NO bioavailability are regulated by multiple post-translational molecular mechanisms, such as eNOS phosphorylation, eNOS interaction with regulatory proteins and contractile pathways, and actions of reactive oxygen species (ROS).…”

Nitric Oxide Induces Pathological Synapse Loss by a Protein Kinase G-, Rho Kinase-Dependent Mechanism Preceded by Myosin Light Chain Phosphorylation

“…Therefore, NO/cGMP/PKG-induced synapse remodeling is dependent on RhoA/ROCK signaling, involving phosphorylation of the ROCK substrate MLC before synapse withdrawal. Increased RhoA/ROCK activity resulting from long-term action of the NO/cGMP/PKG cascade has been previously suggested in arterial smooth muscle cells (Sauzeau et al, 2003), in the penis (Bivalacqua et al, 2007), and in hearts from diabetic rats (Soliman et al, 2008). In this sense, cGMP/PKG together with ROCK and/or MLC-kinase mediates growth cone collapse responses to ephrin-B1, -A5, and Semaphorin 3A in cells from different origins (Dontchev and Letourneau, 2002;Mann et al, 2003;Yue et al, 2008).…”