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October 2002, Volume 14, Number 5, Pages 345-352
Table of contents    Previous  Article  Next   [PDF]
Paper
Implications of nitric oxide synthase isoforms in the pathophysiology of Peyronie's disease
T J Bivalacqua1, H C Champion2 and W J G Hellstrom1

1Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, USA

2Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA

Correspondence to: W J G Hellstrom, Section of Andrology and Male Sexual Dysfunction, Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, USA. E-mail: whellst@tulane.edu

Abstract

Peyronie's disease is an idiopathic, localized connective tissue disorder of the penis which involves the tunica albuginea of the corpus cavernosum and the adjacent areolar space. Peyronie's disease is characterized by local changes in the collagen and elastic fiber composition of the tunica albuginea. The formation of fibrotic plaques alters penile anatomy and can cause different degrees of bending and narrowing, as well as penile pain and erectile dysfunction. Though long recognized as an important clinical entity of the male genitalia, the etiology of this disease has remained poorly understood. Until recently there have been no studies to examine the role nitric oxide (NO) and nitric oxide synthase (NOS) isoforms may play in the onset and progression of Peyronie's disease. NO is a potent biological mediator with diverse physiological and pathophysiological roles. The purpose of this review is to describe each of the NOS isoforms and their potential roles in the pathophysiology of Peyronie's disease, with particular emphasis on the regulation of endothelial and inducible NOS isoforms.

International Journal of Impotence Research (2002) 14, 345-352. doi:10.1038/sj.ijir.3900872

Keywords

Peyronie's; disease; eNOS; iNOS; collagen; erectile dysfunction

Introduction

Peyronie's disease, or induratio plastica, is a penile condition named after Francois Gigot de la Peyronie in 1743. Peyronie's disease can be defined as a localized connective tissue disorder characterized by changes in the collagen composition of the tunica albuginea and corpus cavernosum of the penis. The etiology and pathophysiology of this well-recognized symptom complex have remained undetermined. Peyronie's disease likely involves a sclerosing inflammatory process that invokes localized changes in the histological architecture of the tunica albuginea and adjacent corpus cavernosum of the penis. The sequence of events leading to the fibrosis of the tunica albuginea probably involves the process of injury with subsequent inflammation and infiltration by inflammatory cells and fibrogenic cytokines, followed by tissue repair.1,2,3 The end result is a fibrous plaque that contains an excessive amount of collagen, alterations in its elastin framework, and fibroblastic proliferation. The pathologic changes consequently alter penile anatomy and dramatically affect erectile function. Erectile dysfunction (ED) is recognized to occur in 20-40% of men with Peyronie's disease.4,5,6

Peyronie's disease usually affects males between the fourth and seventh decade of life, with a published 0.39-3.2% incidence.5,6,7 The actual prevalence of this disease is likely to be higher due to patient embarrassment, limited reporting by physicians, and incorrect screening. With increasing numbers of men being successfully treated for ED, many clinicians are observing an increasing number of Peyronie's disease cases. Men with Peyronie's disease commonly complain of any one or combination of the following symptoms: penile pain, penile curvature, palpable plaque, and/or decreased erectile function. The penile curvature is a result of scar tissue or plaque in the tunica albuginea of the corpus cavernosum and is localized to the side of the corpus cavernosum to which the curvature is directed.

There are several proposed theories as to the origin of Peyronie's disease which include: vitamin E deficiency; the use of beta-blocking agents; increased levels of serotonin, as in carcinoid syndrome; genetic disorders; and repetitive vascular trauma inciting a low-level autoimmune response with fibrosis and plaque formation.1,3,8,9,10 Peyronie's patients may have a genetic predisposition, as witnessed by its association with Dupuytren's contracture and HLA-B7 antigens.11,12,13 Other studies have shown chromosomal abnormalities or genetic instability in Peyronie's plaque cells and microsatellite alterations and loss of heterozygosity in Peyronie's disease fibrotic plaques.14 Currently the etiology of Peyronie's disease is thought to originate from an inflammatory process triggered by vascular trauma which results in fibrosis and collagen changes in the penis.1 Following trauma or injury to the penis, the release of fibrogenic cytokines theoretically activates fibroblast proliferation, resulting in collagen deposition and the formation of a Peyronie's plaque. The fibrogenic cytokines transforming growth factor-beta (TGF-beta) and fibroblast growth factor (FGF) are overexpressed in Peyronie's disease tunica albuginea and Peyronie's plaque-derived myofibroblasts.15,16 Therefore, Peyronie's disease has been defined by some authorities as a wound-healing disorder, much like the dermatologic conditions of keloid formation, hypertrophic scarring, and Dupuytren's contracture.2,17

Nitric oxide and nitric oxide synthase

Nitric oxide (NO) is a small reactive free radical, which acts as both an intracellular and extracellular regulatory molecule. Its half-life in most biological systems has been reported to be 2-5 s. NO can freely diffuse through cell membranes to function as a neurotransmitter, a paracrine substance, or an autacoid. Various cellular processes are regulated through the release of NO from the endothelium, platelets, vascular smooth muscle cells, neurons, and other NO-producing cells.18,19 NO has many important physiological roles, including neurotransmission, regulation of vascular tone, penile erection, immunomodulation, and cell-mediated cytotoxicity against pathogens and tumor cells.18,19,20,21 In addition to NO's direct toxic effects, it has been shown to exhibit an inhibitory effect on smooth muscle cell proliferation and collagen synthesis.22

Most tissues can oxidize the guanidino nitrogen of L-arginine to form L-citrulline and NO. NO is rapidly oxidized to the stable, inactive end products nitrite and nitrate. The enzyme that catalyzes this reaction in cells and neurons is termed nitric oxide synthase (NOS).23 At least three distinct forms of NOS have been cloned and characterized (Table 1). The enzyme uses reduced nicotinamide adenine dinucleotide phosphate (NADPH), flavin adenine dinculeotide (FAD), flavin mononucleotide (FMN), and tetrahydrobiopterin (BH4) as cofactors and heme as a prosthetic group. The constitutive forms of the enzyme, neuronal NOS (nNOS; NOS1) and endothelial NOS (eNOS; NOS3), are coupled to Ca2+ and calmodulin and are the principal NOS isoforms involved in the induction of penile erection, while inducible NOS (iNOS; NOS2) is independent of Ca2+ and calmodulin and requires new protein synthesis (Table 1).24,25 eNOS is predominately membrane bound, whereas nNOS is limited to the cytosol of central and peripheral neurons, although its mRNA is also found in skeletal muscle (Table 1).

The concentrations of NO are continually fluctuating at very low levels throughout the body and are controlled by constitutive NOS. eNOS and nNOS are regulated predominately at the post-translational level, whereas iNOS can be expressed in response to an appropriate stimulus or transcriptional factors such as nuclear factor kappa B (NF-kappaB).26 Most of the biological effects of iNOS are through the activation of NF-kappaB response elements in the iNOS gene promoter region.23 iNOS is primarily found in macrophages but is generally believed to be expressed after cytokine induction and in inflammatory pathological states.27,28 Small amounts of NO produced by constitutive NOS from endothelial cells and neurons are involved in signaling events that regulate neurotransmission and vascular tone. Larger concentrations of NO (approximately 100- to 1000-fold more than constitutive NOS) produced from the expression of iNOS are present in cells during infection, inflammation, or after vascular trauma; however, because iNOS is independent of Ca2+ and stimulating agonists, its activity is sustained, which may have beneficial or deleterious effects in biological systems.29,30,31,32 Thus, NO production resulting from the activity of iNOS is more substantial or supraphysiological and, in the presence of cellular superoxide anion (O2-), results in the formation of the highly toxic molecule peroxynitrite (ONOO-) (Figure 1).33 Peroxynitrite is capable of hydroxylating and nitrating aromatic compounds, and inducing cellular injury by: (1) lipid peroxidation; (2) DNA fragmentation, a process which is similar to that of apoptosis; (3) depletion of plasma antioxidants such as glutathione and cysteine; (4) damage and nitration of proteins which can lead to cellular and organ dysfunction; and (5) impairment of endothelial smooth muscle relaxation, as well as alteration of vascular tone.34,35,36,37,38 Additionally, peroxynitrite is less potent than NO as a vasorelaxing agent by several orders of magnitude.39 NO can also react with metals, thiols, and other reactive oxygen species. The reaction of NO and superoxide is 30 times faster than that of NO and oxyhemoglobin and three times faster than the dismutation of superoxide by superoxide dismutase (SOD).40 Therefore, the formation of peroxynitrite is dependent on the balance between the production of superoxide and SOD and NO synthesis/consump-tion. Therefore, low concentrations of NO may modulate or regulate cell function, whereas high NO levels may have a less specific inhibitory or toxic effect on cell function. The most important physiological target of NO is the heme moiety of soluble guanylate cyclase. NO diffuses to adjacent smooth muscle cells stimulating guanylate cyclase (Figure 1). This interaction converts GTP to cyclic GMP (cGMP), which induces a substantial increase in intracellular cGMP causing smooth muscle relaxation, primarily through activation of the cGMP-associated protein kinase (PKGs) and cGMP-dependent ion channels. These second messengers reduce intracellular Ca2+ via Ca2+ sequestration and extrusion, and activation of myosin light chain phosphatases (Figure 1). The physiological actions of cGMP are terminated by the hydrolysis of the 3'5' bond by the type 5 phosphodiesterase. In the penis, NO actions in inducing smooth muscle relaxation via the aforementioned mechanism result in entry of blood and engorgement of the corpus cavernosum and thus cause penile erection.

Nitric oxide synthase and Peyronie's disease

Current proposals as to the origin of Peyronie's disease suggest that collagen deposition and fibrosis of the tunica albuginea and adjacent corpus cavernosum are the result of an inflammatory process following vascular trauma; thus, some authorities have described this condition as a wound healing disorder. However, the exact pathophysiology of Peyronie's disease is not fully delineated and is still under intense investigation.

Wound healing is a complex chain of events involving cellular, biochemical, and molecular mechanisms directed toward restoring tissue integrity and function. The process of wound healing involves an orchestrated sequence of events, including inflammation and infiltration of polymorphonuclear leukocytes (PMNs) and macrophages, followed by a stage of fibroplasia (fibrosis) characterized by granulation of tissue, extracellular matrix deposition, tissue remodeling, angiogenesis, and scarring.17 Local factors which can delay the healing process include mechanical stretching and repetitive manipulation. Fibrosis occurs within the granulation tissue formed at the site of repair and involves two main processes: fibroblast migration and proliferation, and extracellular matrix deposition. A number of growth factors and fibrogenic cytokines, such as platelet derived growth factor (PDGF), fibroblast growth factor (FGF), TGF-beta, interleukin-1 (IL-1), and tumor necrosis factor (TNF-alpha), mediate migration of fibroblasts and their proliferation. As the repair process progresses, the number of proliferating fibroblasts and endothelial cells decreases and the fibroblasts begin to deposit collagen and other components of the extracellular matrix. PDGF, FGF and IL-1 stimulate this collagen synthesis, which are secreted by fibroblasts and leukocytes in the healing wounds.41 TGF-beta is thought to play a particularly important role in chronic inflammatory fibrosis disorders.42 Eventually, the granulation tissue is converted into a scar composed of fibroblasts and collagen. The hallmark feature of Peyronie's disease is increased collagen deposition in the tunica albuginea and corpus cavernosum resulting in a scar or plaque, as well as differentiation of fibroblasts at a time when there is increased expression of TGF-beta and FGF. These findings are consistent with a wound healing disorder. Within the last decade, NOS isoforms, particularly iNOS, have been revealed to modulate the onset and progression of fibroblastic or wound healing disorders.

Wound cells, including monocytes, macrophages, and fibroblasts, have been shown to synthesize NO through an NF-kappaB activated iNOS-dependent mechanism after injury.31,43,44 Whether NO is a mediator of the host's defense or, more importantly, a signal that stimulates cell migration or collagen synthesis is still under debate. The process of wound healing is complex; however, there is conflicting evidence to show that NO production via overexpression of iNOS could be an important mediator of the resolution/suppression of collagen deposition or a stimulator of collagen synthesis in the injured organ.22,45,46,47 Recently, iNOS-deficient mice were shown to have a delay in wound repair which could be reversed by delivery of an adenovirus encoding iNOS cDNA to the wound site.48 Schaffer and colleagues have been able to demonstrate that fibroblasts are phenotypically induced within a wound to synthesize NO.47 Additionally, they demonstrated that wound fibroblasts differ from normal fibroblasts by exhibiting diminished proliferative activity, increased collagen synthesis, and enhanced contractile properties.47,49 Moreover, recent studies indicate that inhibition of iNOS and peroxynitrite scavenging suppresses the course of collagen-induced arthritis, suggesting that iNOS and peroxynitrite formation can contribute to increases in collagen deposition and associated organ dysfunction.49,50 Conversely, there are reports that suggest iNOS expression helps suppress collagen deposition and oppose fibrosis, while iNOS deficiency increases collagen content in atherosclerotic lesions, enhanced production of NO suppresses the development of atherosclerosis.51,52,53 The effect of NO in atherosclerosis is to attenuate smooth muscle cell migration due principally to eNOS, while iNOS acts in the lesion to suppress collagen content.53 Overexpression of iNOS protein and peroxynitrite does occur in the cavernosal tissue and myofibroblasts from Peyronie's disease patients at a time when eNOS protein is unchanged, suggesting that NO production via iNOS does play some role in the pathophysiology of this inflammatory wound healing disorder (Figure 2).54,55,56

In the past, most basic research focused on in vitro models of human cultured Peyronie's plaques, tunica albuginea, and cavernosal tissues. An exciting development has been the recent introduction of an animal model to study the mechanisms of Peyronie's disease in vivo. El-Sakka and colleagues have developed this animal model by directly injecting cytomodulin, an agent that induces production of TGF-beta, and surgically injuring the tunica albuginea of rats, causing a progressive increase in TGF-beta production in the tunica albuginea for up to 6-12 weeks.57,58,59 These studies in the rat penis demonstrate that TGF-beta1 injection and surgical injury to the tunica albuginea can induce symptoms similar to those found in humans suffering from Peyronie's disease. Recently, our laboratory has used this rat model to evaluate erectile function and to examine eNOS and iNOS gene expression as well as NOS activity in the Peyronie's-like rat corpus cavernosum.60,61,62 It has been well documented that the endothelial and neuronal forms of NOS play a prominent role in the physiology of erectile function.20,25,63 However, the role of iNOS in the erectile process is less clear. Recently, Ferrini and colleagues demonstrated a significant increase in iNOS expression, peroxynitrite formation, and apoptosis in aged rats cavernosal tissues.64 These authors concluded that peroxynitrite and apoptosis in the penis could lead to loss of endothelial cells, smooth muscle cells, and nerve tissue, thus altering the physiology of the erectile response. Moreover, overproduction of NO does cause cytotoxicity to human cavernosal smooth muscle cells in culture.65 Inhibition of iNOS in human cavernosal tissue caused enhanced acetylcholine relaxation as well as a negative feedback effect on eNOS in smooth muscle cells grown under inflammatory conditions in vitro.54,66

In studies conducted in our laboratory, Bivalacqua and colleagues found that cavernosal nerve stimulated erectile function and endothelial dependent erectile function of the TGF-beta1-injected and surgical-injury rats when compared to saline-injected rats were significantly reduced in the Peyronie's-like rat experimental groups.60,62 We also found that when erectile function was significantly lower than the control group, there was an increase in calcium-independent NOS activity (inducible) and a decrease in calcium-dependent NOS activity (constitutive), as determined by L-arginine to L-citrulline conversion.60 Western blot analysis of cavernosal tissue obtained from TGF-beta1-injected rats demonstrated a significant increase in iNOS protein expression and immunohistochemical localization of NF-kappaB, as well as a significant decrease in eNOS protein expression when compared to corpus cavernosum obtained from the saline-injected rats.61,62 These studies also found an increase in iNOS gene expression and a decrease in eNOS gene expression, as measured by RT-PCR, in the TGF-beta1-injected rats. However, there was no change in eNOS protein expression in human Peyronie's cavernosal tissue when compared to control tissue, but this may be due to limited control samples and disease status of the Peyronie's patients (Figure 2).55 In order to determine if this increased expression of iNOS could have a deleterious impact on the corpus cavernosum of the rat, we demonstrated an upregulation of nitrotyrosine, the marker for peroxynitrite, in the penis of the TGF-beta1-injected rats.62 These studies were the first to document a role for NO and NOS isoforms in the pathophysiology of erectile dysfunction seen in Peyronie's disease. These results suggest that erectile dysfunction in Peyronie's patients could be due to: (1) alteration of the histological architecture of the tunica albuginea and corpus cavernosum, thus affecting the normal erectile mechanisms; and (2) activation of NF-kappaB and increases in iNOS and nitrotyrosine expression in the corpus cavernosum that may cause alterations in endothelial smooth muscle relaxation, cytotoxicity, and/or apoptosis, thus altering the vascular tone and normal erectile function.

Peyronie's disease is defined as a connective tissue disorder resulting in accumulation of collagen and fibrosis. Recently, the rat model of Peyronie's disease was used to evaluate the role iNOS may play in the regulation of collagen production in the TGF-beta1-injected rats. Ferrini and colleagues demonstrated that inhibition of iNOS resulted in increased deposition of collagen around the TGF-beta1-induced lesions suggesting that iNOS may be suppressing collagen production in Peyronie's disease.56 However, they also found that iNOS induction and NO production in human Peyronie's plaques induced the reactive oxygen species (ROS) hemeoxygenase-1 (HO-1) and nitrotyrosine, as observed by Bivalacqua et al. in the Peyronie's-like rat model, suggesting that NO is interacting with ROS to produce oxidative stress in both human Peyronie's disease and in the Peyronie's-like rat model.56,62 The interaction of NO and superoxide anion and its subsequent production of peroxynitrite has been shown to cause alterations in cavernosal smooth muscle relaxation in both humans and in rats.35,37,39 This situation presents a unique situation in that iNOS expression and subsequent high output NO production may be beneficial in suppressing collagen accumulation in Peyronie's disease but at the same time causes deleterious consequences in the corpus cavernosum, thus altering vascular tone and erectile function. Collectively, these studies unveil a possible mechanism that may be important for the protection of the tunica albuginea and corpus cavernosum from collagen changes, and also a possible mechanism by which there are alterations in the erectile physiology in Peyronie's disease patients.

Summary

Peyronie's disease starts as a sclerosing inflammatory process and develops into a connective tissue disorder involving the tunica albuginea and the corpus cavernosum of the penis. A better understanding of the inflammatory response and the mechanisms by which NOS either inhibits or induces the fibrotic process of the tunica albuginea and corpus cavernosum, as well as NOS's role in the regulation of cavernosal smooth muscle tone will undoubtedly offer new avenues for future medical intervention in Peyronie's disease. Agents that modify NOS expression and cytokine action and ultimately fibroblast function will lead the list in this area of therapeutic investigation.

Acknowledgements

The authors would like to thank Melanie Cross for her assistance in the preparation of this manuscript. This work was supported in part by a Young Investigator Award from the International Society of Impotence Research and Pfizer Inc. and the American Foundation for Urological Diseases to Trinity J. Bivalacqua.

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Figures

Figure 1 General schematic diagram of the actions of nitric oxide in biological systems. NO=nitric oxide; NOS=nitric oxide synthase; NADPH=nicotinamide adenine dinucleotide phosphate; FAD=flavin adenine dinculeotide; FMN=flavin mononucleotide; BH4=tetrahydrobiopterin; GTP=guanosine triphosphate; sGC=soluble guanylate cyclase; cGMP=cyclic guanosine monophosphate; PDE=phosphodiesterase; GMP=guanosine monophosphate; PKG=protein kinase G; ONOO-=peroxynitrite; O2-=superoxide anion; SOD=superoxide dismutase; H2O2=hydrogen peroxide; H2O=water.

Figure 2 Western blot analysis demonstrating expression of iNOS (130 kDa; left) and eNOS (135 kDa; right) protein in cavernosal tissue obtained from control and Peyronie's disease patients. There was a significant increase in iNOS protein expression (P<0.05) in cavernosal tissue of men with Peyronie's disease when compared with control cavernosal tissue obtained from potent men undergoing emergency surgery for penile trauma or correction of congenitial curvature. There was no change in eNOS protein expression (P>0.05) between the two groups of men. Densitometry analysis was determined for iNOS and eNOS (gel unit per milligram of protein) in control and Peyronie's corpus cavernosum. n=8-10; *(P<0.05) value significantly different when compared to control.

Tables

Table 1 Characteristics of the three nitric oxide synthase isoforms

October 2002, Volume 14, Number 5, Pages 345-352
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