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Ed endotlemium

  1. 1. 2390The Endothelial–Erectile Dysfunction Connection:An Essential Update jsm_1356 2390..2404Carla Costa, PhD,*† and Ronald Virag, MD‡*Faculty of Medicine of the University of Porto, Department of Biochemistry (U38-FCT), Porto, Portugal; †Faculty ofMedicine of the University of Porto, Laboratory for Molecular Cell Biology, Porto, Portugal; ‡Centre d’Explorations etTraitements de l’Impuissance (CETI), Paris, FranceDOI: 10.1111/j.1743-6109.2009.01356.xABSTRACTIntroduction. The endothelial monolayer plays a crucial role in the vasodilation and hemodynamic events involvedin erection physiology. Due to its relevant functions, a close link has been established between endothelial integrityand erectile dysfunction (ED). Endothelial dysfunction is induced by the detrimental actions of vascular risk factors(VRFs), identified as common correlates for the development of cardiovascular disease and ED. It is currentlyrecognized that ED is the early harbinger of a more generalized vascular systemic disorder, and, therefore, anevaluation of endothelial health in ED patients should be of prime relevance. Several noninvasive methods forendothelial function assessment have been proposed, including the Penile Nitric Oxide Release Test (PNORT).Aim. To highlight the most recent gathered knowledge on basic and clinical mechanisms underlying loss ofcavernosal endothelial function promoted by VRFs and to discuss local and systemic methods for endothelialfunction assessment in ED individuals, focusing on the PNORT.Main Outcome Measures. A complete revision on the novel basic and clinical links between endothelial and ED.Methods. A systematic review of the literature regarding the aforementioned issues.Results. Risk factor-associated cavernosal endothelial dysfunction is mostly induced by unifying mechanisms,including oxidative stress and impaired endothelial nitric oxide functional activities, which present clinically as ED.Several techniques to evaluate endothelial dysfunction were revised, with advantages and limitations debated,focusing on our detailed expertise using the PNORT method.Conclusions. The established endothelial–erectile dysfunction connection was thoroughly revised, from basicmechanisms to the clinical importance of endothelial dysfunction assessment as diagnosis for generalized vasculardisease. Further studies are required to disclose efficient approaches to repair disabled endothelium and both restoreand prevent endothelial dysfunction. Costa C, and Virag R. The endothelial-erectile dysfunction connection:An essential update. J Sex Med 2009;6:2390–2404.Key Words. Erectile Dysfunction; Endothelial Dysfunction; Vascular Risk Factors; Nitric Oxide; PNORTIntroduction helial cells (ECs). All these cellular components have specific and essential roles in normal erectionE rectile tissue is organized as a mesh of inter- connected cavernous sinusoidal spaces linedwith vascular endothelium and separated by trabe- by controlling the production and release of trans- mitters and mediators that regulate the cascade of events that control the erect vs. flaccid state of thecula, composed of bundles of smooth muscle cells penis [3]. The interplay between the neural, SM,(SMCs), numerous autonomic nerves, and an and endothelial corporeal compartments is crucialextracellular matrix formed by collagen, elastin, for the erection process, and any cellular and/orand fibroblasts [1,2]. Erectogenesis is a phenom- molecular impairment may result in loss of erectileenon that particularly requires neural integrity, function. Although recognizing the relevance ofviable cavernosal SM tissue, and functional endot- the multiple players and integrative events inJ Sex Med 2009;6:2390–2404 © 2009 International Society for Sexual Medicine
  2. 2. The Endothelial–Erectile Dysfunction Connection 2391the complex mechanism of erection, exten- (EDHFs) [12]. These results in engorgement ofsive research has established an irrefutable link the sinusoidal spaces, increase in intracavernousbetween impaired endothelial function and alter- pressure, lengthening and enlargement of theations in normal erectile capability [4–6]. This penis, and compression of the subtunical venules,article will review basic and clinical evidence of allowing the complete occlusion of penile venousimpaired endothelial biological activities in erec- outflow (veno-occlusion) and trapping of bloodtile pathophysiology and the existing noninvasive within the corpus cavernosum (CC). Given thattests that allow endothelial function assessment in penile endothelial health is essential for normalerectile dysfunction (ED). erectile capability, any disruption on corporeal ECs biological actions may affect the arterial and/or veno-occlusive mechanisms, compromisingVascular Endothelium and Penile Erection—A Brief the initiation and/or maintenance of an erectionOverview of the Nitric Oxide/Cyclic Guanosine [13].Monophosphate (NO/cGMP) and AdenylateCyclase/Cyclic Adenosine Monophosphate(AC/cAMP) Signaling Mechanisms Penile Endothelial Cell Function and DysfunctionThe NO/cGMP and AC/cAMP Dependent Pathways Endothelium Physiology and FunctionThe penile circulation is composed of feeder arte- Vascular endothelium is a thin monocellular layerrioles and helicine arteries that empty into a that covers all the inner surface of blood vessels,network of connective tissue surrounding sinusoi- separating circulating blood from the tissues. For-dal cavities lined by SM and ECs [4]. ECs function merly considered as a simple anatomic passivedynamically to regulate the tone of the cavernous barrier, the endothelium is currently recognizedvasculature and subendothelial SM layer. During has a highly metabolically active organ that playssexual arousal or nocturnal tumescence, there is important autocrine, paracrine, and endocrineproduction of neural NO (nNO) through the functions [14]. By the nature of its location, theaction of neuronal NO synthase in cavernosal endothelial monolayer regulates relevant biologi-nerve terminals [7]. nNO is diffused into adjacent cal events, such as the maintenance of balancedcorporeal SM, binding soluble guanylate cyclase vascular pressure, patency and perfusion, inhibi-and increasing intracellular levels of cGMP. tion of thrombosis, induction of fibrinolysis, regu-cGMP interacts with subcellular effector proteins lation of inflammation and platelet aggregation,such as ion channels and protein kinases, particu- and the behavior of the underlying vascular SMlarly protein kinase G-1, reducing SM calcium [15]. Under physiological conditions, to maintainsensitivity to contractile proteins, which eventuate vascular homeostasis, the endothelium has thein SMCs relaxation and in a nNO-mediated inflow capacity to respond to humoral, neuronal, andof arterial blood [8,9]. Effective SMCs relaxation mechanical (in particular, shear stress) stimulimay also be induced through the activation of a through the synthesis and release of a variety ofdifferent cyclic nucleotide pathway, bypassing the endothelium-generated agonist and antagonistnNO route. Different mediators, including neuro- molecules. These factors include procoagulantspeptides such as vasoactive intestinal peptide, and anticoagulants, inflammatory and anti-calcitonin-related peptide, and prostaglandin E1 inflammatory, fibrinolytics and antifibrinolytics,(PGE1), may react with SM membrane specific vasoconstrictors and vasodilators [14,16,17].G-protein-coupled receptors, activating AC, Among those, the equilibrium between vasoactivewhich converts adenosine triphosphate, in the mediators, such as eNO, prostacycline I2, andsecond messenger cAMP [8,10,11]. Increased endothelium-derived EDHFs, and vasoconstric-cAMP induces the relaxation of SM fibers through tors, such as endothelin-1, angiotensin II, prostag-the activation of protein kinase A, resulting in a landin H2, and thromboxane A2, have revealeddecrease in intracellular free calcium, desensitiza- crucial on the regulation of vascular permeability,tion of contractile mechanisms, allowing SMC inflammation and vascular tone [17,18]. Penilerelaxation and arterial blood inflow [10,11]. This endothelial bed is considered as a specializedinitial inflow of blood increases shear stress and extension of the peripheral vascular system,stimulates the phosphorylation of phosphoi- responding similarly to diverse stimuli in order tonositide 3-kinase/endothelial NOS (eNOS) and maintain homeostasis, and playing a particulareNO production, and the release of prostanoids regulatory role on the modulation of vascular andand endothelium-derived hyperpolarizing factors SM contractile tone, crucial for normal erectile J Sex Med 2009;6:2390–2404
  3. 3. 2392 Costa and Viragfunctionality. Considering the important role of in a synergistic fashion, contributing to the exac-intact endothelium, any alterations impairing its erbation of penile and generalized vasculopathybiological activities and disrupting its functional [27]. Considering vasculogenic ED as the “silentintegrity will alter endothelial ability to respond to tip of the iceberg” of a more generalized vascularlocal and systemic changes, a condition referred to disorder may be relevant for the prevention ofas endothelial dysfunction [19]. cardiovascular events in patients with asymptom- atic CAD [21].Endothelial Dysfunction—Pathophysiological Effectson Erection Vascular Risk Factors: Impairing Penile EndothelialThe key feature of endothelial dysfunction is the and Erectile Functiondecreased responsiveness to vasodilator mediatorsor the increased sensitivity to vasoconstrictor As reviewed in Figure 1, risk factor-associated cav-molecules affecting the normal regulatory role of ernosal endothelial alterations are mostly inducedperipheral vascular endothelium, including caver- by unifying mechanisms, including oxidative stressnosal arterial and venous systems. As consequence, and impaired eNOS/eNO functional activities,the vasodilator potential is reduced, and vascular resulting in poor endothelium-dependent vascularstructures are unable to fully dilate in response and SM relaxation, presenting clinically as ED, theto appropriate stimuli. Generally, this decrease particular difficulty in maintaining a firm erection.in endothelial vasodilation is mostly caused bya diminished synthesis and/or lost of eNO Diabetes Mellitusbioavailability/bioactivity in the vasculature [20]. ED is a common complication in men with diabe-Besides vasodilation, eNO-associated alterations tes, affecting up to 75% of all men with the diseasemay also impair a series of relevant mechanisms, [28,29]. In diabetic men, ED occurs at an earlierincluding anticoagulation and anti-inflammatory age than the general population, increasing withactivities, vascular growth, and remodeling capa- disease duration [29]. Hyperglycemia contributesbility [17,20]. Overall, endothelial dysfunction is to metabolic derangements which promote endot-defined by the pathologic impairment of eNO- helial dysfunction and vascular complications [30].dependent vasodilatation and late structural vas- High glucose levels induce the formation of irre-cular abnormalities, a condition considered as versible advanced glycation end products (AGEs),common grounds of both cardiovascular disease affecting endothelial function by several mecha-(CVD) and ED. Additionally, it was suggested that nisms, including targeting of penile eNO, genera-ED may not only be a clinical manifestation of a tion of reactive oxygen species (ROS), and bypathology affecting the penile circulation, but it affecting the expression of endothelial growthmay be a harbinger and a very early warning sign factors [31,32]. These alterations abrogate mul-of a more generalized vascular systemic disorder tiple pathways promoting loss of penile endothe-[21]. The relevance of adequate endothelial func- lium function and ED. AGEs are elevated intion in erection was recognized after the identifi- diabetic penile tissue and interfere with eNO pro-cation of similar vascular risk factors (VRFs) for duction by directly inactivating the phosphoryla-ED and coronary artery disease (CAD), conditions tion of eNOS [31]. ROS formation and increasedthat are highly prevalent and frequently coexist. oxidative stress-associated to AGEs cause CCDiabetes mellitus, hypertension, hypercholester- alterations, including an augment in lipid peroxi-olemia, the more recently recognized metabolic dation, upregulation of superoxide anion (O2–),syndrome (MetS), and aging have been identified and a decrease in antioxidants levels [33,34].as key correlates of ED and CAD, having as Circulating monocytes, which are significantlycommon denominator generalized endothelial increased in diabetic patients with ED, are alsodysfunction, which contributes to the develop- involved in the increased production of ROS [35].ment of atherosclerosis [22–25]. The aforemen- Free radical O2- was shown to interfere with eNOtioned risk factors are responsible for a variety of bioavailability, propagating endothelial dysfunc-endothelial offending insults, numerous biochemi- tion and chronically impairing diabetic penile vas-cal and metabolic alterations, which injure penile cular function [36]. The deleterious effects of ROSlining ECs, constituting a relevant pathophysi- are supported by evidence that superoxide dismu-ologic factor underlying ED [4,22,26]. It has also tase (SOD) gene transfer or treatment with anti-been suggested that the cumulative effects of oxidants reduce superoxide production, increasesseveral VRFs may induce endothelial dysfunction eNO, and restores erectile function in diabetic-J Sex Med 2009;6:2390–2404
  4. 4. The Endothelial–Erectile Dysfunction Connection 2393Figure 1 Mechanisms underlying vascular risk factor-associated endothelial dysfunction. Left panel figures: terminal deoxy-nucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay in human cavernosal tissue from a diabetic ED patientand a control non-diabetic, non-ED individual. Labeled in green: cavernosal ECs in apoptosis detected by TUNEL assay [47];labeled in blue: all cavernosal nuclei stained with DAPI (4′,6-diamidino-2-phenylindole) [47]. ED = erectile dysfunction;AGEs = advanced gycation end products; EC = endothelial cell; eNOS = endothelial nitric oxide synthase; SMCs = smoothmuscle cells; ROS = reactive oxygen species; VEGF = vascular endothelial growth factor. Scale bar = 100 mm.induced animals [33,34,37,38]. Similarly, adenovi- ernosal tissue of diabetic patients with ED haveral gene transfer of eNOS was demonstrated to increased endothelial apoptotic cell density (ACD)improve erectile responses in a diabetic model as compared with nondiabetic non-ED individu-[39]. In diabetic-associated ED, eNO production als. Further, we demonstrated that ACD correlatesis also affected by the RhoA/Rho-kinase signaling with endothelial function assessed in a preopera-system. The vasoconstrictor protein Rho-kinase tive stage by Penile NO Release Test (PNORT)is increasingly expressed in experimental diabetic and duplex scan ecography, and established anCC and downregulates eNOS activity, contribut- important threshold between in situ ACD valuesing to cavernosal endothelial dysfunction and ED and cavernosal endothelial functionality [47].[40]. Penile vasculopathy in diabetics is also asso-ciated to a reduction in the expression of vascular Hypertensionendothelial growth factor (VEGF), a pleiotropic Hypertensive patients have a higher prevalence ofmolecule essential for endothelium homeostasis ED than the general population [48]. Despite the[41]. VEGF expression is diminished in diabetic epidemiologic link between hypertension and ED,corporeal tissue, altering VEGF-mediated intrac- basic science evidence is limited, and the mecha-ellular signaling mechanisms, and leading to nisms leading to penile endothelial dysfunction aredecreased eNOS activation and EC viability [32]. under investigation. Studies in hypertensive pre-Intracavernous therapies with VEGF were clinical models have suggested that high bloodreferred to improve erectile function in diabetic pressure causes morphological changes in penilemodels through the restoration of the insulin-like vascular bed, contributing to erectile failuregrowth factor system and by the amelioration of [49,50]. Further, hypertension-induced ECapoptosis in diabetic CC [42,43]. In fact, scarce mechanical injury and increased oxidative stressdata has suggested that apoptosis may be an impor- are thought to promote endothelial dysfunctiontant mechanism in diabetic ED [44–46]. Our by deleteriously affecting penile ECs-specificgroup has recently shown for the first time how organelles, such as the endoplasmatic reticulumprogrammed cell death affects human diabetic cor- and mitochondria [51]. Oxidative stress and ROSporeal endothelial function. We reported that cav- production are also involved in impaired J Sex Med 2009;6:2390–2404
  5. 5. 2394 Costa and Viragendothelium-dependent vasodilation in hyperten- reported that ED significantly rises with thesion. In a hypertensive model, increased CC levels increased number of metabolic risk factors presentof thiobarbituric acid-reactive substances were concomitantly in a patient [66]. In fact, the accu-detected, and involved in the reduction of eNO- mulation of VRFs, independently recognized asdependent functions, impairing both endothelial detrimental on loss of penile endothelial function,and erectile function [52]. The sources and mecha- may contribute synergistically to the severity ofnisms responsible for ROS formation in hyperten- cavernosal vascular degeneration and ED [27].sion remain mostly unknown; however, it was On a mechanistic level, VRFs’ common groundssuggested that ROS increase might be mediated by leading to endothelial dysfunction involve anits enzymatic production by adenine dinucleotide augment in oxidative stress and decreased eNOS/phosphate (NADPH) oxidase and by alterations in eNO activation/bioavailability, as aforementioned.intracellular antioxidant enzymes, including SOD However, other pathologic elements of the syn-[53,54]. Accordingly, diminished SOD activity has drome may deleteriously affect additional path-been observed in hypertensive rat corporeal tissue, ways of the vascular biology of the penis. A recentimplicating this mechanism in ROS formation study using a strain of obese-diabetic rats, mimick-associated to hypertensive ED [54]. ing MetS phenotype and metabolic alterations, has attempted to elucidate how the combination ofHypercholesterolemia several VRFs contributes to cavernosal endothelialHypercholesterolemia is considered an indepen- dysfunction. This report has shown that in MetSdent risk factor for ED development, contributing animals, there is also an increase in endothelium-to the degeneration of the penile vascular bed [55]. produced Rho-kinase protein, which enhancesStudies demonstrated that hypercholesterolemia vasoconstriction mechanisms [67]. Although thecauses a reduction in normal CC vasoreactivity, epidemiological link between MetS and ED ismostly by decreasing local eNOS/eNO activity irrefutable, further cellular and molecular studiesand bioavailability [56,57]. Impaired eNOS are required to unveil additional endothelial-function/eNO production in the hypercholester- associated pathways impaired and involved in ED.olemic cavernosal vasculature has been mostlyattributed to O2- production, potentially mediated Agingby increased NADPH oxidase expression/activity It is established that the incidence of ED increases[58]. Oxidized low-density lipoprotein has also with the advancement of age [68]. Vasculogenicbeen implicated in ED, since its presence has been erectile impairment with aging was suggested toidentified in corporeal structures, including ECs, involve penile vascular structural alterationsand considered a causative factor for impaired CC [69,70]. Additionally, loss of endothelial functionrelaxation responses [59]. Hypercholesterolemia has been reported in elderly CC due to alterationsmay also affect penile endothelial function by in eNO bioavailability, increased oxidative stress,altering the homeostatic expression of vascular altered vascular growth factor expression, andgrowth factors. Studies in hypercholesterole- increase in activity of the RhoA/Rho-kinasemic models have demonstrated that VEGF, pathway [71–74]. The association between oxida-angiopoietin-1, and -2 were downregulated in cor- tive stress and age-related ED was established byporeal tissue [56,60]. Further, single or combined the observation that experimental aging cavernosalintracavernous therapies with endothelial growth endothelium produces high levels of O2-. Accord-factors resulted in increased vasoreactivity in ingly, intracavernous SOD gene transfer in agedhypercholesterolemic cavernosal tissue and animals reduces O2- formation, restoring erec-improvement of erectile function [61–63]. tile function [72]. Similarly, impaired eNOS expression/activity in the aged penis may beMetabolic Syndrome (MetS) improved by local eNOS therapy, augmentingMetS is a highly prevalent condition in industrial- erectile responses [71]. In fact, downregulation ofized countries, manifested by the collective com- eNO in elderly CC has been thoroughly reportedbination of several VRFs for CVD and ED, and related to a decrease in VEGF expression [74],including obesity, hyperglycemia, hypertension, an increase in endothelial activity of arginase,and lipidic alterations [64]. Clinical studies have the enzyme that competes with eNOS for theestablished an association between MetS and ED, common substrate L-arginine (L-Arg) [75], andbeing both conditions linked by abnormal endot- with a deregulation in eNOS activation due to ahelial function [65,66]. Additionally, it was also decreased phosphorylation of its positive regula-J Sex Med 2009;6:2390–2404
  6. 6. The Endothelial–Erectile Dysfunction Connection 2395tory site (Ser-1177) and an increased phosphory- evaluate endothelium-dependent, as well aslation of its negative regulatory site (Thr-495) endothelium-independent vasodilation. This[76]. In addition, eNOS physiology may be method involves the ultrasonographic measure-affected by an increased release/activity of Rho- ment of the brachial artery diameter before andkinase in aged penis, a fact corroborated by the after a 5-minute occlusion of the forearm bloodimprovement of erectile function through the flow induced by inflation and deflation of a proxi-inhibition of the RhoA/Rho-kinase pathway [73]. mal upper arm cuff [78]. The result is increasedBesides the aforementioned mechanisms associat- blood flow, shear stress-mediated NO release, anding endothelial dysfunction with aged ED, we endothelium-dependent vasodilation, generallymust also have into account that with the advance- determined as the percentage change from thement of age, there is an accumulation of VRFs, baseline measurement to the artery diameter atwhich might exacerbate penile endothelial dys- 40–60 seconds after cuff deflation. Additionally,function and age-related ED. FMD endothelium-independent SMC-mediated Efforts to disclose basic mechanisms involved in vasodilation can be assessed by sublingual admin-cavernosal endothelial dysfunction allied to the istration of nitroglycerin (NTG) and measuringabovementioned conditions is essential in order to the diameter of the artery three times at 5 minutespropose novel tailored adjuvant therapies. Addi- post-NTG intake. SM-modulated vasodilation istionally, it is essential to verify in vivo the effects of defined as the percentage change from restingimpaired endothelial mediators and intracellular baseline artery diameter to the average of thepathways in EC function in men with ED. The three post-NTG diameters [79]. Both FMD testsbasis underlying this important evaluation is the are valuable and used to specifically identifyrecognition of endothelial dysfunction as a biom- endothelial-associated vasodilation dysfunction,arker of atherosclerosis and generalized vascular SM relaxation alterations, and vasodilation im-disease, being ED the first clinical manifestation. pairment. To evaluate solely vascular reactivityAs so, it is crucial to determine in ED patients through an endothelial response, it is commonlysystemic and local endothelial functional abnor- used the endothelium-dependent FMD analysis.malities in the vascular bed using, developing, and FMD has become a standard test to assess thefurther improving noninvasive clinical methods. interplay between VRFs, endothelial function and CVD, and, more recently, to evaluate ED patients [6,80,81]. Studies have suggested that endothelialClinical Evaluation of Endothelial (Dys)Function in function detected on the brachial artery correlatesED Patients with function in conduit coronary arteries, estab-When clinically evaluating endothelial function in lishing a link between endothelial-dependentED patients, there are two inherent challenges: FMD and CAD [82]. Given that VRFs areone involves the assessment of general endothelial common grounds for the development of bothfunction, linking ED with a more generalized CAD and ED, it was not surprising that severalprocess of vascular deterioration, and the second is studies have related impaired FMD and vasculo-to study local endothelium injury by assessing genic ED in populations with CVD and/or one orpenile endothelial dysfunction. For both purposes, several risk factors, confirming our early pioneer-there are several hemodynamic and biological ing statement considering erectile failure mostly asevaluation tools, with advantages and limitations a vascular disease [6,26,83]. Concordantly, patientsthat will be further discussed. with vasculogenic ED were shown to present more coronary atherosclerosis than control individualsHemodynamic Evaluation of Systemic [84]. More interesting are reports demonstratingEndothelial Dysfunction that FMD detected endothelial dysfunction inFlow-Mediated Dilation (FMD) men with ED, but without the presence of anySince the early nineties, it has been demonstrated clinically established vascular disease. This hasthat postischemic vasodilatation in the medium raised the main interest of systemic endotheliallarge arteries is dependent largely on an function measurements in ED patients: the diag-endothelium-derived NO response [77]. Based on nosis of preatherosclerotic states [79,84]. In addi-this concept, vascular reactivity tests were devel- tion to an endothelial FMD dysfunction, the sameoped and established for clinical assessment of study has also showed that SM-induced vasodila-endothelial function. FMD of the brachial artery is tion was impaired. Nonetheless, the relevance ofthe most widely used noninvasive technique to this systemic endothelium-independent alteration J Sex Med 2009;6:2390–2404
  7. 7. 2396 Costa and Viragon erectile capability should be further assessed Biological Evaluation of Endothelial Function inspecifically and thoroughly in the penis. The FMD Peripheral Bloodtechnique, although reliable, has reproducibilityproblems and some limitations particularly related Serum Markersto the mandatory ultrasonografic expertise, the To date, many circulating biomarkers have beensignificant day-to-day variability (approximately proposed for the evaluation of endothelial func-25%) due to the biological circadian rhythm, tion; however, none have been considered the idealvariations on the baseline diameter of the artery, or more specific, and most are unavailable forand postprandial opposed to fasting state [78,85]. current practice [82]. Serum markers of inflamma- tion and cellular adhesion, underlying the impor-Peripheral Arterial Tonometry (PAT) tance of these processes in early atherosclerosis,This new noninvasive technique is based on bilat- are the most commonly used to assess endothelialeral comparative digital plethysmography. It dysfunction. Among the inflammatory markers,involves the plethysmographic recording of the C-reactive protein (CRP) and endothelin-1 (ET-1)arterial pulse wave amplitude at both index finger- are used to determine loss of EC function. Accord-tips using stiff finger cuffs with air-inflatable pres- ingly, elevated levels of CRP have been associatedsure chambers. The PAT signal is recorded in one with impaired endothelial function, cardiovascularindex finger after postocclusive reactive hyperemia events, and ED [89]. Increased ET-1 has also been(RHI), induced by a cuff on the upper arm, and linked to endothelial dysfunction manifested bycompared with values obtained on other hand at the presence of ED [90]. Additionally, circulatingthe equivalent finger. PAT signals are processed levels of cellular adhesion molecules, such as selec-using specific software, and the results are ex- tins, intercellular adhesion molecule-1, vascularpressed as index of RHI (EndoPat; Itamar Medical cell adhesion molecule-1 (VCAM-1), have alsoLtd, Caesarea, Israel) [86]. Accordingly, endothe- been associated with endothelial dysfunction andlial dysfunction is ruled out when RHI values are increased risk of CAD and ED [91]. The assess-above 2.07, and considered if RHI is below 1.67. ment of asymetric dimethylarginine (ADMA)In between these two values lies a gray area, which blood levels is also a used method. Increased levelsrepresents a sensitive zone predisposing to future of ADMA, which is a competitive inhibitor of vas-development of endothelial dysfunction. In addi- cular eNOS, have been associated to the patho-tion, besides assessing endothelial function, the genesis of vascular endothelial dysfunction, andPAT evaluation software can also be used for spe- established a close link between CAD and EDcific measurements of arterial stiffness [86]. PAT [92,93]. ADMA concentrations seemed directlyhas been used to evaluate early and clinically rel- correlated to other methods of endothelialevant CAD, and the results showed a correlation dysfunction evaluation, such as endothelium-with coronary endothelial function [87]. A recent dependent FMD [94]. Additionally, the assessmentstudy from the Framingham heart study group has of the L-Arg/ADMA ratio might also be a valuablerelated the measurements by this technique to the tool for the evaluation of specific alterations onpresence of VRFs [88]. In fact, PAT can be a very endothelial function [92]. Recent studies have alsouseful method in the evaluation of conditions as suggested that increasing levels of homocysteinediabetes or the MetS, given that similarly to seem related to a decrease in eNO synthesis and toendothelium-dependent FMD, it seems to repre- a decrease in erectile function [95]. Nonetheless,sent a true physiological reflection of peripheral and besides being a minimal invasive test, usingEC function. This relevant tool has recently peripheral blood, which is easily drawn, there arestarted to be used for the evaluation of patients some setbacks in the clinical usability of these cir-with ED [26], and is currently being applied for culating biomarkers. For instance, the systemicthose purposes in our institution. The advantage increase in proinflammatory and cell adhesionof this procedure when compared with FMD is molecules might be an acute and transient eventthat it requires less specialized training, and the induced by other pathophysiological processes,obtained results are automatic and totally operator and their correlation with endothelial dysfunctionindependent. However, PAT accuracy may lead to status has to be carefully established. In addition,conflicting results, particularly in patients with low the discovery of other markers more sophisticatedpressure and low flow states, and therefore further and used under various regimens and treatments,additional studies are required to validate the clini- have been reported, but not directly associatedcal use of this methodology. with other endothelial function measurements,J Sex Med 2009;6:2390–2404
  8. 8. The Endothelial–Erectile Dysfunction Connection 2397Figure 2 Cavernosal artery endothelium-dependent FMD assessed by PNORT in a non-ED individual. (A) Preocclusion(basal artery diameter measurement = 0.6 mm); (B) postocclusion endothelial response (average diameter measure-ment = 0.92 mm). The difference between pre- and postocclusion is 0.32 mm, and the percentage increase is 53% (normalresponse). FMD = flow-mediated dilation; PNORT = Penile Nitric Oxide Release Test; ED = erectile dysfunction.particularly with brachial FMD, in ED individuals Hemodynamic Evaluation of Penile[96]. Endothelial Function PNORTCellular Markers Penile anatomical and vascular characteristics ledIn case of vascular endothelium damage, either us to establish a standardized test, the PNORT,mechanically or by the noxious action of VRFs, which could specifically measure in cavernosalthere is a rapid need to reestablish endothelial arteries the endothelium-dependent capacity tointegrity and vascular homeostasis. Efficient vasodilate, giving an estimation of the arterialendothelium repair involves the activation of the response mediated by locally produced eNO.vasculogenic mechanism, by which bone marrow- Based on the same principles as the endothelium-derived endothelial progenitor cells (EPCs) are dependent FMD in the forearm artery, this non-mobilized and recruited to the peripheral circula- invasive technique consists on the ultrasonographiction, and to the site of injury where they differen- measurement of the pre- and postocclusive diam-tiate into mature ECs, helping to regenerate the eter of one of the cavernous arteries. Similarly,affected monolayer [97]. However, the vasculo- cavernosal artery diameter is measured before andgenesis process was shown to be impaired in CVD, after a 5-minute occlusion of penile blood flowas reduced levels of circulating EPCs (cEPCs) induced by a specific cuff (Figure 2) [102,103].were detected and related to endothelial dysfunc- Determination of the arterial endothelial responsetion and to future cardiovascular events [98]. capacity is calculated as for brachial or radialAdditionally, low numbers of cEPCs were found in FMD. The FMD in cavernous arteries is strongerCAD patients and correlated with erectile function than in the forearm arteries, and, accordingly,in the same population [99]. Other studies confirm non-ED and nonorganic ED subjects were shownthe presence of lower cEPCs in patients with ED, to have an average increase of 68% in the diameterconfirming the existence of an endothelial dys- of the cavernosal arteries as compared with afunction and supplying evidence that ED may 5–10% augment in the radial arteries [79,102]. Inbe the first symptom of a systemic endothelial opposition to the significant increase of PNORTdamage [100]. A recent report demonstrated that in healthy penile vascular beds, organic diseasedcEPCs levels were reduced in overweight men cavernosal endothelium presents a lower responsewith ED and correlated with the severity of erec- to this test. This may be explained in certain casestile failure [101]. The direct quantification of by the histological detection of a higher endothe-cEPCs may represent a novel noninvasive surro- lial apoptotic rate [47]. Interestingly, it was alsogate marker for vascular homeostasis/dysfunction, observed that postradical prostatectomy EDED and CVD. However, the determination of patients presented a severe decreased response tocEPCs performed by flow cytometry only indi- PNORT, which was comparable or even lower tocates the peripheral circulating number of this the PNORT detected on the most diseased vascu-progenitor cell population, and additional studies logenic ED patients [104]. This suggests that theare required for further information on impaired NO pathways after radical prostatectomy arecEPCs function. impaired or abrogated, affecting several erectile J Sex Med 2009;6:2390–2404
  9. 9. 2398 Costa and Viragcellular and molecular mechanisms, including penile diagnosis. Additionally, the arterial stiffnessendothelial function. Another valuable finding is can also be studied by further ultrasound evalua-the significant difference observed in PNORT tion of the cavernous arteries after intracavernousresults in different groups of patients such as, injection of vasoactive medications (i.e., PGE1).non-ED or nonvascular ED individuals with orwithout VRFs [103]. Moreover, some ED patients Penile Veno-Occlusive Plethysmographyconsidered nonorganic with normal arterial, neu- In a recent publication, changes in blood flow inrologic, and hormonal evaluation, seem to present both arms and penis were evaluated by veno-a low response to PNORT, indicator of a previ- occlusive plethysmography. The authors sug-ously undiscovered early sign of systemic endothe- gested the use of postischemic changes in bloodlial dysfunction (R Virag, unpublished data). In the flow in both arms and penis to assess endothelialfuture, comparative measurements of systemic function using essentially the calculation of theendothelial function by FMD or PAT and penile area under the flow-time curve. They observed aendothelial function by PNORT should identify if significant difference between ED and non-EDboth values are strictly correlated, and/or answer patients at the penile level, but not in the forearmto the question: does specific penile endothelial [105]. Albeit this is, at first, promising data, itdysfunction exist? A recent work using matching appears noticeable that their ED and non-EDsystemic and penile veno-occlusive plethysmogra- patient groups were not age matched, and nophy corroborates this idea [105], however, previ- information was disclosed concerning their vascu-ous data has suggested some discrepancies [106]. lar characteristics. The penile flow measurementsLarger series comparing RHI and PNORT in ED with veno-occlusive plethysmography might beand non-ED patients are necessary to understand somewhat cumbersome due to the fact that veno-if a specific or earlier specific penile endothe- occlusion in the resting penis is not easy. Actually,lial dysfunction exists. Our previous findings the basal blood flow in the penis is different in[102,103] and ongoing studies (R Virag, unpub- both study groups, raising questions of a bias in thelished data) have encouraged us to recommend this real meaning of the amplitude of the flow postoc-local hemodynamic test as a first-line evaluation clusive decrease. Further and larger studies in EDtool for endothelial function in any individual are needed to evaluate the accuracy of this tech-presenting ED symptoms. In patients presenting nique, which is already in use for neuroanatomicalone or more VRFs, the decrease of the PNORT studies of volume increase evaluation under visualresponse seems to have a prognostic value, and in sexual stimulation [107].those free of VRFs, the discovery of a low PNORTresponse should lead to a more complete and Therapeutic Relevance of Endothelial Dysfunctiondetailed evaluation. PNORT can be easily per- in ED Patientsformed in conjunction with PAT measurements,and it might also become a good means for the The strong link established between endothelialfollow-up of protective or repairing treatments for dysfunction and ED suggests that the use ofendothelial dysfunction. Although PNORT pre- certain medications and supplements may improvesents the same bias drawback as the systemic FMD concomitantly endothelial and erectile function.measurements, specially the correlation between Statins, intracavernous injections of vasoactivethe basal diameter of the cavernous artery and its agents and phosphodiesterase 5 inhibitorspercentage of increase, it is a reliable and repro- (PDE5I) are the most frequently cited for thisducible technique, being an excellent noninvasive effect [108–110]. Additionally, we have recentlytool to evaluate penile endothelial function at early reported [111] an increase of endothelial function,stages of vascular disease. Additionally, it allows to assessed by PNORT, in a series of patients after 2assess the degree of severity of diseased endothe- months intake of a mixture of L-Arg, SOD andlium and to diagnose an initial stage of systemic grape extract (Elliovir; Laboratoire Ellios Bio Tek,endothelial dysfunction, manifested as prema- Paris, France). Studies showed that chronic intaketure ED with deleterious endothelium function. of the PDE5I tadalafil significantly reduced serumThe use of PNORT to assess endothelium- levels of CRP, ET-1, and VCAM-1, and improvedindependent FMD in cavernous arteries might both ED and endothelium-dependent FMD mea-also be an additional testing essential to evaluate surements of penile arteries [112]. Additionally,SMC functional capacity and complement the the same therapeutic regimen with tadalafilendothelial analysis establishing a more accurate resulted in an increase in cEPCs mobilization andJ Sex Med 2009;6:2390–2404
  10. 10. The Endothelial–Erectile Dysfunction Connection 2399ameliorated endothelial function, as assessed by be performed in conjunction with a thoroughFMD [113]. Another report demonstrated a posi- local penile vascular evaluation. Nonetheless,tive correlation between PNORT increase and endothelial-erectile function seem tightly con-erection improvement after vardenafil therapy nected, and there is a growing concern for an[114]. Accordingly and considering our histologi- earlier protection of both penile and systemiccal [47] and clinical studies [104], we assume that endothelium through the alteration of lifestylethe response to PDE5I might be correlated to the behaviors, allowing the control of VRFs, comple-PNORT. Below a certain PNORT value, indica- mented with specific endothelial-rehabilitatingtive of severe endothelium injury, the drugs are less compounds. Concerns to their sexual capabilityprone to be effective. Most importantly, the iden- should be for many young men a strong motiva-tification of endothelial dysfunction manifested tion to quit smoking, bad alimentary habits, andearlier by ED is an alert of a potential development help to protect them from life-threatening vascu-of systemic vascular disease and must be taken into lar diseases.account. In populations at risk and when endothe-lial dysfunction is detected by ED symptoms,besides therapeutic intervention, it is crucial to Acknowledgmentsestablish early preventive measures, such as CC was supported by the Portuguese Foundation forchanges in lifestyle habits (smoking, alcohol, high Science and Technology (PTDC/SAU-OSM/65599/caloric food). 2006). Corresponding Author: Carla Costa, PhD, FacultyConclusions of Medicine of the University of Porto, Department of Biochemistry (U38-FCT), Porto, Portugal. Tel:Endothelium dysfunction and ED are definitely +351 225513654; Fax: +351 225513655; E-mail:linked as Siamese twins. VRFs are implicated in carcosta@med.up.ptendothelial deleterious alterations, affectingprimordially the eNO-dependent vasodilation Conflict of Interest: None.pathway, which severely injure penile lining ECs,disturbing also their important interaction with Statement of Authorshipother erectile components, such as the SM layer.Importantly, endothelial dysfunction may be Category 1manifested initially by ED, which is considered as (a) Conception and Designan early-warning sign for the development of ath- Carla Costa; Ronald Viragerosclerosis and CVD. The noninvasive assess- (b) Acquisition of Datament of peripheral and local endothelial function Carla Costa; Ronald Viragin the office setting is currently available, allowing (c) Analysis and Interpretation of Data Carla Costa; Ronald Viragthe diagnosis of endothelial dysfunction and vas-culogenic ED. Although with advantages and limi-tations, these evaluation tools have demonstrated Category 2that early diagnosis of ED may have preventive (a) Drafting the Articlevalue on future cardiovascular events and can also Carla Costa; Ronald Virag (b) Revising It for Intellectual Contentbe used as predictive tests regarding therapeutic Carla Costa; Ronald Viragresponse. As so, we suggest PNORT as theprimary local exam to determine vasculogenicED, in conjunction with brachial endothelium- Category 3dependent FMD or digital PAT assessment of sys- (a) Final Approval of the Completed Article Carla Costa; Ronald Viragtemic endothelial function. In addition, a completepenile evaluation should be complemented withthe assessment of endothelium-independent, ReferencesSMC-derived FMD measurement in cavernous 1 Porst H, Sharlip ID. Anatomy and physiology ofbodies in order to establish a more accurate diag- erection. In: Porst H, Buvat J, eds. Standard Prac-nosis between the two major components of erec- tice in Sexual Medicine. West Sussex: Blackwelltion. Our expertise lead us to consider that Publishing; 2006:31–42.systemic noninvasive methods of endothelial func- 2 Goldstein AM, Meehan JP, Morrow JW, Buckleytion are extremely valuable, but they should always PA, Rogers FA. The fibrous skeleton of the corpora J Sex Med 2009;6:2390–2404
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