Recently published work has supported the emerging concept that the vascular and sinusoidal endothelium and, specifically, endothelial nitric oxide synthase (eNOS) localized to this cellular structure play important roles in aspects of the vascular homeostasis and erection physiology of the penis. Investigations of eNOS in the penis have shown that the enzyme is activated by a specific phosphorylation mechanism under blood flow stimulation so that it releases the gaseous messenger molecule nitric oxide (NO) in a steady, continuous manner. This finding indicates that eNOS contributes significantly to NO-mediated penile erection, regulating the penile tumescence and erection maintenance phases of the erectile response. Further investigation has revealed that eNOS is deficient in the penis under various conditions associated with erectile dysfunction including diabetes and aging. These reports correspond with epidemiologic studies that have identified high rates of erectile dysfunction in individuals with cardiovascular diseases, leading to suggestions of a common pathogenic link: endothelial dysfunction. However, the precise mechanisms underlying the putatively defective endothelial function in the penis associated with vasculogenic erectile dysfunction remain poorly understood. It is hypothesized that the actions of eNOS in the penis under the control of various complex regulatory mechanisms have an impact on the endothelial-dependent biological functions of this organ. Accordingly, this research proposal centers on two areas, the investigation of several specific molecular mechanisms controlling eNOS actions in the penis in correlation with physiologic and pathophysiologic events of this organ, and the assessment of """"""""activated"""""""" eNOS as a vasculoprotective molecular target for preserving penile vascular function.
Specific aims are: (1) to characterize eNOS isoform-specific regulatory mechanisms (i.e., post-translational phosphorylation, protein-protein interactions) operating in the penis during physiologic penile flaccidity and erection in the rat; (2) to determine roles of eNOS isoform-specific regulatory mechanisms in the penis in the pathogenesis of atherosclerosis-associated erectile dysfunction using porcine and rodent animal models; (3) to determine roles of eNOS isoform-specific regulatory mechanisms in the penis in the pathogenesis of age-associated erectile dysfunction in the rat; and (4) to evaluate """"""""activated"""""""" eNOS as a molecular target for improving erectile function using select interventions (i.e., growth factor therapy, pharmacoinduction, and gene transfer) in rodent animal models of vasculogenic erectile dysfunction. The work may advance treatments not only for erectile dysfunction, but also for disorders of endothelial dysfunction in general.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RUS-B (03))
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Rankin, Tracy L
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Johns Hopkins University
Schools of Medicine
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La Favor, Justin D; Fu, Zongming; Venkatraman, Vidya et al. (2018) Molecular Profile of Priapism Associated with Low Nitric Oxide Bioavailability. J Proteome Res 17:1031-1040
Musicki, Biljana; Bhunia, Anil K; Karakus, Serkan et al. (2018) S-nitrosylation of NOS pathway mediators in the penis contributes to cavernous nerve injury-induced erectile dysfunction. Int J Impot Res 30:108-116
Musicki, B; Burnett, A L (2017) Constitutive NOS uncoupling and NADPH oxidase upregulation in the penis of type 2 diabetic men with erectile dysfunction. Andrology 5:294-298
Matsui, Hotaka; Musicki, Biljana; Sopko, Nikolai A et al. (2017) Early-stage Type 2 Diabetes Mellitus Impairs Erectile Function and Neurite Outgrowth From the Major Pelvic Ganglion and Downregulates the Gene Expression of Neurotrophic Factors. Urology 99:287.e1-287.e7
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Akakpo, William; Musicki, Biljana; Burnett, Arthur L (2017) cAMP-dependent regulation of RhoA/Rho-kinase attenuates detrusor overactivity in a novel mouse experimental model. BJU Int 120:143-151
Musicki, B; Hannan, J L; Lagoda, G et al. (2016) Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats. Andrology 4:977-83
Musicki, Biljana; Lagoda, Gwen; Goetz, Tabitha et al. (2016) Transnitrosylation: A Factor in Nitric Oxide-Mediated Penile Erection. J Sex Med 13:808-814
Silva, Fábio H; Karakus, Serkan; Musicki, Biljana et al. (2016) Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment. J Pharmacol Exp Ther 359:230-237
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