Ed endotlemium

2390

The Endothelial–Erectile Dysfunction Connection:
An Essential Update jsm_1356 2390..2404

Carla Costa, PhD,*† and Ronald Virag, MD‡
*Faculty of Medicine of the University of Porto, Department of Biochemistry (U38-FCT), Porto, Portugal; †Faculty of
Medicine of the University of Porto, Laboratory for Molecular Cell Biology, Porto, Portugal; ‡Centre d’Explorations et
Traitements de l’Impuissance (CETI), Paris, France

DOI: 10.1111/j.1743-6109.2009.01356.x

ABSTRACT

Introduction. The endothelial monolayer plays a crucial role in the vasodilation and hemodynamic events involved
in erection physiology. Due to its relevant functions, a close link has been established between endothelial integrity
and 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 currently
recognized that ED is the early harbinger of a more generalized vascular systemic disorder, and, therefore, an
evaluation of endothelial health in ED patients should be of prime relevance. Several noninvasive methods for
endothelial 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 of
cavernosal endothelial function promoted by VRFs and to discuss local and systemic methods for endothelial
function 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 basic
mechanisms to the clinical importance of endothelial dysfunction assessment as diagnosis for generalized vascular
disease. Further studies are required to disclose efficient approaches to repair disabled endothelium and both restore
and 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; PNORT

Introduction helial cells (ECs). All these cellular components
have specific and essential roles in normal erection

E rectile tissue is organized as a mesh of inter-
connected cavernous sinusoidal spaces lined
with 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 the
cula, 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 crucial
extracellular matrix formed by collagen, elastin, for the erection process, and any cellular and/or
and fibroblasts [1,2]. Erectogenesis is a phenom- molecular impairment may result in loss of erectile
enon that particularly requires neural integrity, function. Although recognizing the relevance of
viable cavernosal SM tissue, and functional endot- the multiple players and integrative events in

J Sex Med 2009;6:2390–2404 © 2009 International Society for Sexual Medicine

The Endothelial–Erectile Dysfunction Connection 2391

the complex mechanism of erection, exten- (EDHFs) [12]. These results in engorgement of
sive research has established an irrefutable link the sinusoidal spaces, increase in intracavernous
between impaired endothelial function and alter- pressure, lengthening and enlargement of the
ations 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 venous
impaired endothelial biological activities in erec- outflow (veno-occlusion) and trapping of blood
tile pathophysiology and the existing noninvasive within the corpus cavernosum (CC). Given that
tests that allow endothelial function assessment in penile endothelial health is essential for normal
erectile dysfunction (ED). erectile capability, any disruption on corporeal
ECs biological actions may affect the arterial
and/or veno-occlusive mechanisms, compromising
Vascular Endothelium and Penile Erection—A Brief the initiation and/or maintenance of an erection
Overview of the Nitric Oxide/Cyclic Guanosine
[13].
Monophosphate (NO/cGMP) and Adenylate
Cyclase/Cyclic Adenosine Monophosphate
(AC/cAMP) Signaling Mechanisms Penile Endothelial Cell Function and Dysfunction
The NO/cGMP and AC/cAMP Dependent Pathways Endothelium Physiology and Function
The penile circulation is composed of feeder arte- Vascular endothelium is a thin monocellular layer
rioles 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 passive
dynamically to regulate the tone of the cavernous barrier, the endothelium is currently recognized
vasculature and subendothelial SM layer. During has a highly metabolically active organ that plays
sexual arousal or nocturnal tumescence, there is important autocrine, paracrine, and endocrine
production of neural NO (nNO) through the functions [14]. By the nature of its location, the
action 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 balanced
corporeal 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 SM
larly protein kinase G-1, reducing SM calcium [15]. Under physiological conditions, to maintain
sensitivity to contractile proteins, which eventuate vascular homeostasis, the endothelium has the
in SMCs relaxation and in a nNO-mediated inflow capacity to respond to humoral, neuronal, and
of arterial blood [8,9]. Effective SMCs relaxation mechanical (in particular, shear stress) stimuli
may also be induced through the activation of a through the synthesis and release of a variety of
different cyclic nucleotide pathway, bypassing the endothelium-generated agonist and antagonist
nNO route. Different mediators, including neuro- molecules. These factors include procoagulants
peptides 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 vasoactive
which converts adenosine triphosphate, in the mediators, such as eNO, prostacycline I2, and
second 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 revealed
decrease in intracellular free calcium, desensitiza- crucial on the regulation of vascular permeability,
tion of contractile mechanisms, allowing SMC inflammation and vascular tone [17,18]. Penile
relaxation and arterial blood inflow [10,11]. This endothelial bed is considered as a specialized
initial 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 to
nositide 3-kinase/endothelial NOS (eNOS) and maintain homeostasis, and playing a particular
eNO production, and the release of prostanoids regulatory role on the modulation of vascular and
and endothelium-derived hyperpolarizing factors SM contractile tone, crucial for normal erectile

J Sex Med 2009;6:2390–2404

2392 Costa and Virag

functionality. Considering the important role of in a synergistic fashion, contributing to the exac-
intact endothelium, any alterations impairing its erbation of penile and generalized vasculopathy
biological activities and disrupting its functional [27]. Considering vasculogenic ED as the “silent
integrity will alter endothelial ability to respond to tip of the iceberg” of a more generalized vascular
local and systemic changes, a condition referred to disorder may be relevant for the prevention of
as endothelial dysfunction [19]. cardiovascular events in patients with asymptom-
atic CAD [21].
Endothelial Dysfunction—Pathophysiological Effects
on Erection
Vascular Risk Factors: Impairing Penile Endothelial
The key feature of endothelial dysfunction is the
and Erectile Function
decreased responsiveness to vasodilator mediators
or 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 induced
peripheral vascular endothelium, including caver- by unifying mechanisms, including oxidative stress
nosal arterial and venous systems. As consequence, and impaired eNOS/eNO functional activities,
the vasodilator potential is reduced, and vascular resulting in poor endothelium-dependent vascular
structures are unable to fully dilate in response and SM relaxation, presenting clinically as ED, the
to appropriate stimuli. Generally, this decrease particular difficulty in maintaining a firm erection.
in endothelial vasodilation is mostly caused by
a diminished synthesis and/or lost of eNO Diabetes Mellitus
bioavailability/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 disease
may also impair a series of relevant mechanisms, [28,29]. In diabetic men, ED occurs at an earlier
including anticoagulation and anti-inflammatory age than the general population, increasing with
activities, vascular growth, and remodeling capa- disease duration [29]. Hyperglycemia contributes
bility [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 by
pathology affecting the penile circulation, but it affecting the expression of endothelial growth
may 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 in
tion 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 increased
that are highly prevalent and frequently coexist. oxidative stress-associated to AGEs cause CC
Diabetes 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 significantly
common denominator generalized endothelial increased in diabetic patients with ED, are also
dysfunction, 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 eNO
tioned 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 ROS
lining 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, increases
several VRFs may induce endothelial dysfunction eNO, and restores erectile function in diabetic-

J Sex Med 2009;6:2390–2404


Figure 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 patient
and 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 = smooth
muscle 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 have
ral 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 correlates
is 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 an
CC and downregulates eNOS activity, contribut- important threshold between in situ ACD values
ing 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 Hypertension
endothelial growth factor (VEGF), a pleiotropic Hypertensive patients have a higher prevalence of
molecule 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 are
decreased eNOS activation and EC viability [32]. under investigation. Studies in hypertensive pre-
Intracavernous therapies with VEGF were clinical models have suggested that high blood
referred to improve erectile function in diabetic pressure causes morphological changes in penile
models through the restoration of the insulin-like vascular bed, contributing to erectile failure
growth factor system and by the amelioration of [49,50]. Further, hypertension-induced EC
apoptosis in diabetic CC [42,43]. In fact, scarce mechanical injury and increased oxidative stress
data has suggested that apoptosis may be an impor- are thought to promote endothelial dysfunction
tant mechanism in diabetic ED [44–46]. Our by deleteriously affecting penile ECs-specific
group has recently shown for the first time how organelles, such as the endoplasmatic reticulum
programmed cell death affects human diabetic cor- and mitochondria [51]. Oxidative stress and ROS
poreal endothelial function. We reported that cav- production are also involved in impaired

J Sex Med 2009;6:2390–2404


endothelium-dependent vasodilation in hyperten- reported that ED signiﬁcantly rises with the
sion. In a hypertensive model, increased CC levels increased number of metabolic risk factors present
of 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 as
dependent 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 of
nisms 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 grounds
suggested that ROS increase might be mediated by leading to endothelial dysfunction involve an
its 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 recent
implicating 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 of
Hypercholesterolemia several VRFs contributes to cavernosal endothelial
Hypercholesterolemia is considered an indepen- dysfunction. This report has shown that in MetS
dent 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 enhances
Studies demonstrated that hypercholesterolemia vasoconstriction mechanisms [67]. Although the
causes a reduction in normal CC vasoreactivity, epidemiological link between MetS and ED is
mostly by decreasing local eNOS/eNO activity irrefutable, further cellular and molecular studies
and 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 mostly
attributed to O2- production, potentially mediated Aging
by 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]. Vasculogenic
been implicated in ED, since its presence has been erectile impairment with aging was suggested to
identiﬁed in corporeal structures, including ECs, involve penile vascular structural alterations
and considered a causative factor for impaired CC [69,70]. Additionally, loss of endothelial function
relaxation responses [59]. Hypercholesterolemia has been reported in elderly CC due to alterations
may also affect penile endothelial function by in eNO bioavailability, increased oxidative stress,
altering the homeostatic expression of vascular altered vascular growth factor expression, and
growth factors. Studies in hypercholesterole- increase in activity of the RhoA/Rho-kinase
mic 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 by
poreal tissue [56,60]. Further, single or combined the observation that experimental aging cavernosal
intracavernous therapies with endothelial growth endothelium produces high levels of O2-. Accord-
factors resulted in increased vasoreactivity in ingly, intracavernous SOD gene transfer in aged
hypercholesterolemic 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 be
Metabolic Syndrome (MetS) improved by local eNOS therapy, augmenting
MetS is a highly prevalent condition in industrial- erectile responses [71]. In fact, downregulation of
ized countries, manifested by the collective com- eNO in elderly CC has been thoroughly reported
bination 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 the
established an association between MetS and ED, common substrate L-arginine (L-Arg) [75], and
being both conditions linked by abnormal endot- with a deregulation in eNOS activation due to a
helial function [65,66]. Additionally, it was also decreased phosphorylation of its positive regula-

J Sex Med 2009;6:2390–2404


tory site (Ser-1177) and an increased phosphory- evaluate endothelium-dependent, as well as
lation 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 and
kinase in aged penis, a fact corroborated by the after a 5-minute occlusion of the forearm blood
improvement 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 increased
Besides the aforementioned mechanisms associat- blood flow, shear stress-mediated NO release, and
ing endothelial dysfunction with aged ED, we endothelium-dependent vasodilation, generally
must also have into account that with the advance- determined as the percentage change from the
ment of age, there is an accumulation of VRFs, baseline measurement to the artery diameter at
which 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 measuring
abovementioned conditions is essential in order to the diameter of the artery three times at 5 minutes
propose novel tailored adjuvant therapies. Addi- post-NTG intake. SM-modulated vasodilation is
tionally, it is essential to verify in vivo the effects of defined as the percentage change from resting
impaired endothelial mediators and intracellular baseline artery diameter to the average of the
pathways in EC function in men with ED. The three post-NTG diameters [79]. Both FMD tests
basis underlying this important evaluation is the are valuable and used to specifically identify
recognition 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 reactivity
As so, it is crucial to determine in ED patients through an endothelial response, it is commonly
systemic 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 the
further 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 endothelial
Clinical Evaluation of Endothelial (Dys)Function in
function detected on the brachial artery correlates
ED Patients
with function in conduit coronary arteries, estab-
When clinically evaluating endothelial function in lishing a link between endothelial-dependent
ED patients, there are two inherent challenges: FMD and CAD [82]. Given that VRFs are
one involves the assessment of general endothelial common grounds for the development of both
function, linking ED with a more generalized CAD and ED, it was not surprising that several
process 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 or
penile endothelial dysfunction. For both purposes, several risk factors, confirming our early pioneer-
there are several hemodynamic and biological ing statement considering erectile failure mostly as
evaluation tools, with advantages and limitations a vascular disease [6,26,83]. Concordantly, patients
that will be further discussed. with vasculogenic ED were shown to present more
coronary atherosclerosis than control individuals
Hemodynamic Evaluation of Systemic [84]. More interesting are reports demonstrating
Endothelial Dysfunction that FMD detected endothelial dysfunction in
Flow-Mediated Dilation (FMD) men with ED, but without the presence of any
Since the early nineties, it has been demonstrated clinically established vascular disease. This has
that postischemic vasodilatation in the medium raised the main interest of systemic endothelial
large 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 same
oped 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 of
the most widely used noninvasive technique to this systemic endothelium-independent alteration

J Sex Med 2009;6:2390–2404


on erectile capability should be further assessed Biological Evaluation of Endothelial Function in
specifically and thoroughly in the penis. The FMD Peripheral Blood
technique, although reliable, has reproducibility
problems and some limitations particularly related Serum Markers
to the mandatory ultrasonografic expertise, the To date, many circulating biomarkers have been
significant 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 ideal
variations on the baseline diameter of the artery, or more specific, and most are unavailable for
and 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 endothelial
eral 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 associated
sure chambers. The PAT signal is recorded in one with impaired endothelial function, cardiovascular
index 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 by
compared with values obtained on other hand at the presence of ED [90]. Additionally, circulating
the 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, vascular
pressed as index of RHI (EndoPat; Itamar Medical cell adhesion molecule-1 (VCAM-1), have also
Ltd, Caesarea, Israel) [86]. Accordingly, endothe- been associated with endothelial dysfunction and
lial 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 levels
represents 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, and
PAT evaluation software can also be used for spe- established a close link between CAD and ED
cific measurements of arterial stiffness [86]. PAT [92,93]. ADMA concentrations seemed directly
has been used to evaluate early and clinically rel- correlated to other methods of endothelial
evant CAD, and the results showed a correlation dysfunction evaluation, such as endothelium-
with coronary endothelial function [87]. A recent dependent FMD [94]. Additionally, the assessment
study from the Framingham heart study group has of the L-Arg/ADMA ratio might also be a valuable
related the measurements by this technique to the tool for the evaluation of specific alterations on
presence of VRFs [88]. In fact, PAT can be a very endothelial function [92]. Recent studies have also
useful method in the evaluation of conditions as suggested that increasing levels of homocysteine
diabetes or the MetS, given that similarly to seem related to a decrease in eNO synthesis and to
endothelium-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, using
EC function. This relevant tool has recently peripheral blood, which is easily drawn, there are
started 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 systemic
those purposes in our institution. The advantage increase in proinflammatory and cell adhesion
of this procedure when compared with FMD is molecules might be an acute and transient event
that it requires less specialized training, and the induced by other pathophysiological processes,
obtained results are automatic and totally operator and their correlation with endothelial dysfunction
independent. 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 sophisticated
pressure 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 associated
cal use of this methodology. with other endothelial function measurements,

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Figure 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% (normal
response). 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
PNORT
Cellular Markers Penile anatomical and vascular characteristics led
In 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 cavernosal
there is a rapid need to reestablish endothelial arteries the endothelium-dependent capacity to
integrity and vascular homeostasis. Efficient vasodilate, giving an estimation of the arterial
endothelium 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 ultrasonographic
tion, 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 and
genesis process was shown to be impaired in CVD, after a 5-minute occlusion of penile blood flow
as 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 response
tion and to future cardiovascular events [98]. capacity is calculated as for brachial or radial
Additionally, low numbers of cEPCs were found in FMD. The FMD in cavernous arteries is stronger
CAD 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 shown
the presence of lower cEPCs in patients with ED, to have an average increase of 68% in the diameter
confirming the existence of an endothelial dys- of the cavernosal arteries as compared with a
function and supplying evidence that ED may 5–10% augment in the radial arteries [79,102]. In
be the first symptom of a systemic endothelial opposition to the significant increase of PNORT
damage [100]. A recent report demonstrated that in healthy penile vascular beds, organic diseased
cEPCs levels were reduced in overweight men cavernosal endothelium presents a lower response
with ED and correlated with the severity of erec- to this test. This may be explained in certain cases
tile 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 also
gate marker for vascular homeostasis/dysfunction, observed that postradical prostatectomy ED
ED and CVD. However, the determination of patients presented a severe decreased response to
cEPCs performed by flow cytometry only indi- PNORT, which was comparable or even lower to
cates 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 the
are required for further information on impaired NO pathways after radical prostatectomy are
cEPCs function. impaired or abrogated, affecting several erectile

J Sex Med 2009;6:2390–2404


cellular and molecular mechanisms, including penile diagnosis. Additionally, the arterial stiffness
endothelial 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 intracavernous
results in different groups of patients such as, injection of vasoactive medications (i.e., PGE1).
non-ED or nonvascular ED individuals with or
without VRFs [103]. Moreover, some ED patients Penile Veno-Occlusive Plethysmography
considered nonorganic with normal arterial, neu- In a recent publication, changes in blood flow in
rologic, 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 blood
lial dysfunction (R Virag, unpublished data). In the flow in both arms and penis to assess endothelial
future, comparative measurements of systemic function using essentially the calculation of the
endothelial function by FMD or PAT and penile area under the flow-time curve. They observed a
endothelial function by PNORT should identify if significant difference between ED and non-ED
both values are strictly correlated, and/or answer patients at the penile level, but not in the forearm
to the question: does specific penile endothelial [105]. Albeit this is, at first, promising data, it
dysfunction exist? A recent work using matching appears noticeable that their ED and non-ED
systemic and penile veno-occlusive plethysmogra- patient groups were not age matched, and no
phy corroborates this idea [105], however, previ- information was disclosed concerning their vascu-
ous data has suggested some discrepancies [106]. lar characteristics. The penile flow measurements
Larger series comparing RHI and PNORT in ED with veno-occlusive plethysmography might be
and 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 the
lished 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 ED
tool 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 neuroanatomical
one or more VRFs, the decrease of the PNORT studies of volume increase evaluation under visual
response seems to have a prognostic value, and in sexual stimulation [107].
those free of VRFs, the discovery of a low PNORT
response should lead to a more complete and
Therapeutic Relevance of Endothelial Dysfunction
detailed evaluation. PNORT can be easily per-
in ED Patients
formed in conjunction with PAT measurements,
and it might also become a good means for the The strong link established between endothelial
follow-up of protective or repairing treatments for dysfunction and ED suggests that the use of
endothelial dysfunction. Although PNORT pre- certain medications and supplements may improve
sents the same bias drawback as the systemic FMD concomitantly endothelial and erectile function.
measurements, specially the correlation between Statins, intracavernous injections of vasoactive
the basal diameter of the cavernous artery and its agents and phosphodiesterase 5 inhibitors
percentage of increase, it is a reliable and repro- (PDE5I) are the most frequently cited for this
ducible technique, being an excellent noninvasive effect [108–110]. Additionally, we have recently
tool 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 2
assess the degree of severity of diseased endothe- months intake of a mixture of L-Arg, SOD and
lium 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 intake
ture ED with deleterious endothelium function. of the PDE5I tadalafil significantly reduced serum
The use of PNORT to assess endothelium- levels of CRP, ET-1, and VCAM-1, and improved
independent 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 tadalafil
endothelial analysis establishing a more accurate resulted in an increase in cEPCs mobilization and

J Sex Med 2009;6:2390–2404


ameliorated endothelial function, as assessed by be performed in conjunction with a thorough
FMD [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 systemic
cal [47] and clinical studies [104], we assume that endothelium through the alteration of lifestyle
the 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-rehabilitating
tive of severe endothelium injury, the drugs are less compounds. Concerns to their sexual capability
prone 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, and
earlier 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 Acknowledgments
establish early preventive measures, such as CC was supported by the Portuguese Foundation for
changes in lifestyle habits (smoking, alcohol, high Science and Technology (PTDC/SAU-OSM/65599/
caloric food). 2006).

Corresponding Author: Carla Costa, PhD, Faculty
Conclusions 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.pt
endothelial deleterious alterations, affecting
primordially the eNO-dependent vasodilation Conflict of Interest: None.
pathway, which severely injure penile lining ECs,
disturbing also their important interaction with Statement of Authorship
other erectile components, such as the SM layer.
Importantly, endothelial dysfunction may be Category 1
manifested initially by ED, which is considered as (a) Conception and Design
an early-warning sign for the development of ath- Carla Costa; Ronald Virag
erosclerosis and CVD. The noninvasive assess- (b) Acquisition of Data
ment of peripheral and local endothelial function Carla Costa; Ronald Virag
in the office setting is currently available, allowing (c) Analysis and Interpretation of Data
Carla Costa; Ronald Virag
the diagnosis of endothelial dysfunction and vas-
culogenic ED. Although with advantages and limi-
tations, these evaluation tools have demonstrated Category 2
that early diagnosis of ED may have preventive (a) Drafting the Article
value on future cardiovascular events and can also Carla Costa; Ronald Virag
(b) Revising It for Intellectual Content
be used as predictive tests regarding therapeutic
response. As so, we suggest PNORT as the
primary local exam to determine vasculogenic
ED, in conjunction with brachial endothelium-
Category 3
dependent FMD or digital PAT assessment of sys- (a) Final Approval of the Completed Article
temic endothelial function. In addition, a complete
penile evaluation should be complemented with
the assessment of endothelium-independent, References
SMC-derived FMD measurement in cavernous 1 Porst H, Sharlip ID. Anatomy and physiology of
bodies 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: Blackwell
tion. Our expertise lead us to consider that Publishing; 2006:31–42.
systemic noninvasive methods of endothelial func- 2 Goldstein AM, Meehan JP, Morrow JW, Buckley
tion are extremely valuable, but they should always PA, Rogers FA. The fibrous skeleton of the corpora

J Sex Med 2009;6:2390–2404


cavernosa and its probable function in the mecha- 19 Behrendt D, Ganz P. Endothelial function. From
nism of erection. Br J Urol 1985;144:575–8. vascular biology to clinical applications. Am J
3 Sáenz de Tejada I, Angulo J, Cellek S, González- Cardiol 2002;90:40L–8L.
Cadavid N, Heaton J, Pickard R, Simonsen U. 20 Maxwell AJ. Mechanisms of dysfunction of the
Physiology of erectile function. J Sex Med 2004;1: nitric oxide pathway in vascular diseases. Nitric
254–65. Oxide 2002;6:101–24.
4 Bivalacqua TJ, Usta MF, Champion HC, Kadow- 21 Montorsi P, Montorsi F, Schulman CC. Is erectile
itz PJ, Hellstrom WJ. Endothelial dysfunction in dysfunction the “tip of the iceberg” of a systemic
erectile dysfunction: Role of the endothelium vascular disorder? Eur Urol 2003;44:352–4.
in erectile physiology and disease. J Androl 2003; 22 Kirby M, Jackson G, Simonsen U. Endothelial
24:S17–37. dysfunction links erectile dysfunction to heart
5 Goldstein I. The association of ED (erectile dys- disease. Int J Clin Pract 2005;59:225–9.
function) with ED (endothelial dysfunction) in 23 Hartge MM, Kintscher U, Unger T. Endothelial
the International Journal of Impotence Research: The dysfunction and its role in diabetic vascular disease.
Journal of Sexual Medicine. Int J Impot Res Endocrinol Metab Clin North Am 2006;35:551–
2003;15:229–30. 60.
6 Kaya C, Uslu Z, Karaman I. Is endothelial function 24 Wassink AM, Olijhoek JK, Visseren FL. The meta-
impaired in erectile dysfunction patients? Int J bolic syndrome: Metabolic changes with vascular
Impot Res 2006;18:55–60. consequences. Eur J Clin Invest 2007;37:8–17.
7 Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, 25 Versari D, Daghini E, Virdis A, Ghiadoni L,
Snyder SH. Nitric oxide: A physiologic mediator Taddei S. The aging endothelium, cardiovascular
of penile erection. Science 1992;257:401–3. risk and disease. Exp Physiol. 2009;94:317–21.
8 Andersson KE. Pharmacology of penile erection. 26 Yavuzgil O, Altay B, Zoghi M, Gürgün C, Kay-
Phamacol Rev 2001;53:417–50. ikçioglu M, Kültürsay H. Endothelial function in
˘
9 Hedlund P, Szodi A, Pfeifer A, Alm P, Hofman F, patients with vasculogenic erectile dysfunction. Int
Ahmas M, Fassler R, Andersson KE. Erectile dys- J Cardiol 2005;103:19–26.
function in cyclic GMP-dependent kinase-I- 27 Kendirci M, Nowfar S, Hellstrom WJ. The impact
deficient mice. Proc Natl Acad Sci USA 2000;97: of vascular risk factors on erectile function. Drugs
2349–54. Today (Barc) 2005;41:65–74.
10 Porst H. The rationale for prostaglandin E1 in 28 Saenz T. Pathophysiology of erectile dysfunction.
erectile failure: A survey of worldwide experience. J Sex Med 2005;2:26–39.
J Urol 1996;155:802–15. 29 Chaiban JT, Azar ST. Erectile dysfunction in dia-
11 Virag R, Ottesen B, Levy C, Wagner G. Vasoactive betic patients. J Med Liban 2004;52:217–9.
intestinal polypeptide release during penile erec- 30 Brownlee M. Biochemistry and molecular cell
tion in man. Lancet 1982;2:1166. biology of diabetic complications. Nature 2001;
12 Hurt KJ, Musicki B, Palese MA, Crone JK, Becker 414:813–20.
RE, Moriarity JL, Snyder SH, Burnett AL. Akt- 31 Musicki B, Kramer MF, Becker RE, Burnett AL.
dependent phosphorylation of endothelial nitric- Inactivation of phosphorylated endothelial nitric
oxide synthase mediates penile erection. Proc Natl oxide synthase (Ser-1177) by O-GlcNAc in
Acad Sci USA 2002;99:4061–6. diabetes-associated erectile dysfunction. Proc Natl
13 Siroky MB, Azadzoi KM. Vasculogenic erectile Acad Sci USA 2005;102:11870–5.
dysfunction: Newer therapeutic strategies. J Urol 32 Jesmin S, Sakuma I, Salah-Eldin A, Nonomura K,
2003;170:S24–30. Hattori Y, Kitabatake A. Diminished penile
14 Lerman A, Burnett JC Jr. Intact and altered endot- expression of vascular endothelial growth factor
helium in regulation of vasomotion. Circulation and its receptors at the insulin-resistant stage of a
1992;86:III12–9. type II diabetic rat model: A possible cause for
15 Esper RJ, Nordaby RA, Vilariño JO, Paragano A, erectile dysfunction in diabetes. J Mol Endocrinol
Cacharrón JL, Machado RA. Endothelial dysfunc- 2003;31:401–18.
tion: A comprehensive appraisal. Cardiovasc Dia- 33 Bivalacqua TJ, Usta MF, Kendirci M, Pradhan L,
betol 2006;5:4. Alvarez X, Champion HC, Kadowitz PJ, Hell-
16 Villar IC, Francis S, Webb A, Hobbs AJ, Ahluwalia strom WJ. Superoxide anion production in the rat
A. Novel aspects of endothelium-dependent regu- penis impairs erectile function in diabetes: influ-
lation of vascular tone. Kidney Int 2006;70:840– ence of in vivo extracellular superoxide dismutase
53. gene therapy. J Sex Med 2005;2:187–97.
17 Endemann DH, Schiffrin EL. Endothelial dys- 34 Tuncayengin A, Biri H, Onaran M, Sen I, Tuncay-
function. J Am Soc Nephrol 2004;15:1983–92. engin O, Polat F, Erbas D, Bozkirli I. Cavernosal
18 Pober JS, Sessa WC. Evolving functions of endot- tissue nitrite, nitrate, malondialdehyde and glu-
helial cells in inflammation. Nat Rev Immunol tathione levels in diabetic and non-diabetic erectile
2007;7:803–15. dysfunction. Int J Androl 2003;26:250–4.

J Sex Med 2009;6:2390–2404


35 Morano S, Gatti A, Mandosi E, Tiberti C, Fal- microparticles in diabetic and nondiabetic men
larino M, Cipriani R, Buchetti B, Gandini L, Sgrò with erectile dysfunction. J Sex Med 2008;5:1436–
P, Jannini EA, Lenti L, Lenzi A. Circulating 42.
monocyte oxidative activity is increased in patients 47 Costa C, Soares R, Castela A, Adães S, Hastert V,
with type 2 diabetes and erectile dysfunction. Vendeira P, Virag R. Increased endothelial apop-
J Urol 2007;177:655–9. totic cell density in human diabetic erectile
36 Jones RW, Rees RW, Minhas S, Ralph D, Persad tissue—comparison with clinical data. J Sex Med
RA, Jeremy JY. Oxygen free radicals and the penis. 2008;6:826–35.
Expert Opin Pharmacother 2002;3:889–97. 48 Jensen J, Lendorf A, Stimpel H, Frost J, Ibsen H,
37 Keegan A, Cotter MA, Cameron NE. Effects Rosenkilde P. The prevalence and etiology of
of diabetes and treatment with the antioxidant impotence in 101 male hypertensive outpatients.
alpha-lipoic acid on endothelial and neurogenic Am J Hypertens 1999;12:271–5.
responses of corpus cavernosum in rats. Diabeto- 49 Okabe H, Hale TM, Kumon H, Heaton JP, Adams
logia 1999;42:343–50. MA. The penis is not protected in hypertension
38 De Young L, Yu D, Bateman RM, Brock GB. there are vascular changes in the penis which are
Oxidative stress and antioxidant therapy: Their similar to those in other vascular beds. Int J Impot
impact in diabetes-associated erectile dysfunction. Res 1999;11:133–40.
J Androl 2004;25:830–6. 50 Behr-Roussel D, Chamiot-Clerc P, Bernabe J,
39 Bivalacqua TJ, Usta MF, Champion HC, Adams Mevel K, Alexandre L, Safar ME, Giuliano F.
D, Namara DB, Abdel-Mageed AB, Kadowitz PJ, Erectile dysfunction in spontaneously hyperten-
Hellstrom WJ. Gene transfer of endothelial nitric sive rats: Pathophysiological mechanisms. Am J
oxide synthase partially restores nitric oxide syn- Physiol Regul Integr Comp Physiol 2003;284:
thesis and erectile function in streptozotocin dia- R682–8.
betic rats. J Urol 2003;169:1911–7. 51 Jiang R, Chen JH, Jin J, Shen W, Li QM. Ultra-
40 Bivalacqua TJ, Champion HC, Usta MF, Cellek S, structural comparison of penile cavernous tissue
Chitaley K, Webb RC, Lewis RL, Mills TM, Hell- between hypertensive and normotensive rats. Int J
strom WJ, Kadowitz PJ. RhoA/Rho-kinase sup- Impot Res 2005;17:417–23.
presses endothelial nitric oxide synthase in the 52 Ushiyama M, Morita T, Kuramochi T, Yagi S,
penis: A mechanism for diabetes-associated erectile Katayama S. Erectile dysfunction in hypertensive
dysfunction. Proc Natl Acad Sci USA 2004;101: rats results from impairment of the relaxation
9121–6. evoked by neurogenic carbon monoxide and nitric
41 Ferrara N. Role of vascular endothelial growth oxide. Hypertens Res 2004;27:253–61.
factor in regulation of physiological angiogenesis. 53 Jin L, Lagoda G, Leite R, Webb RC, Burnett AL.
Am J Physiol Cell Physiol 2001;280:C1358–66. NADPH oxidase activation: A mechanism of
42 Shirai M, Yamanaka M, Shiina H, Igawa M, hypertension-associated erectile dysfunction. J Sex
Kawakami T, Ishii N, Lue TF, Fujime M, Dahiya Med 2008;5:544–51.
R. Vascular endothelial growth factor restores 54 Ushiyama M, Kuramochi T, Yagi S, Katayama S.
erectile function through modulation of the Antioxidant treatment with alpha-tocopherol
insulin-like growth factor system and sex hormone improves erectile function in hypertensive rats.
receptors in diabetic rat. Biochem Biophys Res Hypertens Res 2008;31:1007–13.
Commun 2006;341:755–62. 55 Feldman HA, Johannes CB, Derby CA, Kleinman
43 Yamanaka M, Shirai M, Shiina H, Tanaka Y, KP, Mohr BA, Araujo AB, McKinlay JB. Erectile
Enokida H, Tsujimura A, Matsumiya K, Okuyama dysfunction and coronary risk factors: Prospective
A, Dahiya R. Vascular endothelial growth factor results from the Massachusetts male aging study.
restores erectile function through inhibition of Prev Med 2000;30:328–38.
apoptosis in diabetic rat penile crura. J Urol 56 Xie D, Odronic SI, Wu F, Pippen AM, Donatucci
2005;173:318–23. CF, Annex BH. A mouse model of
44 Seftel AD, Maclennan GT, Chen ZJ, Liu S, hypercholesterolemia-induced erectile dysfunc-
Ferguson K, Deoreo G, Levine F, Hampel N, tion. J Sex Med 2007;4:898–07.
Ho-Chang C. Loss of TGFbeta, Apoptosis, and 57 Seo KK, Yun HY, Kim H, Kim SC. Involvement of
Bcl-2 in Erectile Dysfunction and Upregulation of endothelial nitric oxide synthase in the impaired
p53 and HIF-1alpha in Diabetes-Associated Erec- endothelium-dependent relaxation of cavernous
tile Dysfunction. Mol Urol 1999;3:103–7. smooth muscle in hypercholesterolemic rabbit.
45 Liu J, Xia R, Fu W, Chen Y, Liu G. Apoptosis and J Androl 1999;20:298–06.
hemodynamic changes of the penile tissue in dia- 58 Kim SC, Kim IK, Seo KK, Baek KJ, Lee MY.
betic rats. Zhonghua Nan Ke Xue 2004;10:445–8. Involvement of superoxide radical in the impaired
46 Esposito K, Ciotola M, Giugliano F, Sardelli L, endothelium-dependent relaxation of cavernous
Giugliano F, Maiorino MI, Beneduce F, De Sio M, smooth muscle in hypercholesterolemic rabbits.
Giugliano D. Phenotypic assessment of endothelial Urol Res 1997;25:341–6.

J Sex Med 2009;6:2390–2404


59 Zouaoui Boudjeltia K, Roumeguere T, Delree P, 72 Bivalacqua TJ, Armstrong JS, Biggerstaff J, Abdel-
Moguilevsky N, Ducobu J, Vanhaeverbeek M, Mageed AB, Kadowitz PJ, Hellstrom WJ, Cham-
Wespes E. Presence of LDL modified by myelop- pion HC. Gene transfer of extracellular SOD to
eroxidase in the penis in patients with vascular the penis reduces O2-* and improves erectile func-
erectile dysfunction: A preliminary study. Eur Urol tion in aged rats. Am J Physiol Heart Circ Physiol
2007;51:262–8. 2003;284:H1408–21.
60 Ryu JK, Shin HY, Song SU, Oh SM, Piao S, Han 73 Rajasekaran M, White S, Baquir A, Wilkes N.
JY, Park KW, Suh JK. Downregulation of angio- Rho-kinase inhibition improves erectile function
genic factors and their downstream target mol- in aging male Brown-Norway rats. J Androl 2005;
ecules affects the deterioration of erectile function 26:182–8.
in a rat model of hypercholesterolemia. Urology 74 Rajasekaran M, Kasyan A, Jain A, Kim SW, Monga
2006;67:1329–34. M. Altered growth factor expression in the aging
61 Byrne RR, Henry GD, Rao DS, Huynh TT, penis: The Brown-Norway rat model. J Androl
Pippen AM, Annex BH, Hagen PO, Donatucci 2002;23:393–9.
CF. Vascular endothelial growth factor restores 75 Bivalacqua TJ, Burnett AL, Hellstrom WJ, Cham-
corporeal smooth muscle function in vitro. J Urol pion HC. Overexpression of arginase in the
2001;165:1310–5. aged mouse penis impairs erectile function and
62 Xie D, Pippen AM, Odronic SI, Annex BH, decreases eNOS activity: Influence of in vivo gene
Donatucci CF. Intracavernosal basic fibroblast therapy of anti-arginase. Am J Physiol Heart Circ
growth factor improves vasoreactivity in the hyper- Physiol 2007;292:H1340–51.
cholesterolemic rabbit. J Sex Med 2006;3:223–32. 76 Musicki B, Kramer MF, Becker RE, Burnett AL.
63 Ryu JK, Cho CH, Shin HY, Song SU, Oh SM, Lee Age-related changes in phosphorylation of endot-
M, Piao S, Han JY, Kim IH, Koh GY, Suh JK. helial nitric oxide synthase in the rat penis. J Sex
Combined angiopoietin-1 and vascular endothelial Med 2005;2:347–55.
growth factor gene transfer restores cavernous 77 Joannides R, Haefeli WE, Linder L, Richard V,
angiogenesis and erectile function in a rat model Bakhali EH, Thuilliez C, Luscher TF. Nitric
of hypercholesterolemia. Mol Ther 2006;13:705– Oxide is responsible for flow-dependent dilation of
15. human peripheral conduit arteries in vivo. Circu-
64 Expert Panel on Detection, Evaluation, and Treat- lation 1995;91:1314–9.
ment of High Blood Cholesterol in Adults (Adult 78 Corretti MC, Anderson TJ, Benjamin EJ, Celerma-
Treatment Panel III). Executive summary of the jer D, Charbonneau F, Creager MA, Deanfield J,
Third Report of the National Cholesterol Educa- Drexler H, Gerhard-Herman M, Herrington D,
tion Program (NCEP). JAMA 2001;285:2486–97. Vallance P, Vita J, Vogel R, International Brachial
65 Esposito K, Giugliano F, Martedì E, Feola G, Artery Reactivity Task Force. Guidelines for the
Marfella R, D’Armiento M, Giugliano D. High ultrasound assessment of endothelial-dependent
proportions of erectile dysfunction in men with flow-mediated vasodilation of the brachial artery: A
the metabolic syndrome. Diabetes Care 2005;28: report of the International Brachial Artery Reactiv-
1201–3. ity Task Force. J Am Coll Cardiol 2002;39:257–65.
66 Demir T. Prevalence of erectile dysfunction in 79 Kaiser DR, Billups K, Mason C, Wetterling R,
patients with metabolic syndrome. Int J Urol 2006; Lundberg JL, Bank AJ. Impaired brachial artery
13:385–8. endothelium dependent and independent vasodila-
67 Wingard C, Fulton D, Husain S. Altered penile tation in men with erectile dysfunction and no
vascular reactivity and erection in the Zucker other clinical cardiovascular factor. J Am Coll
obese-diabetic rat. J Sex Med 2007;4:348–62. Cardiol 2004;43:179–84.
68 Monga M. The aging penis: Erectile dysfunction. 80 Fronek A, Allison M. Non-invasive assessment of
Geriatr Nephrol Urol 1999;9:27–37. endothelial activity in patients with coronary heart
69 Ruzbarsky V, Michal V. Morphologic changes in disease and cardiovascular risk factors. Vasa
the arterial bed of the penis with aging. Relation- 2008;37:137–42.
ship to the pathogenesis of impotence. Invest Urol 81 Tamler R, Bar-Chama N. Assesment of endothelial
1977;15:194–9. function in the patient with erectile dysfunction:
70 Costa C, Vendeira P. Does erectile tissue angioar- An opportunity for the urologist. Int J Impot Res
chitecture modify with aging? An immunohisto- 2008;20:1–8.
logical and morphometric approach. J Sex Med 82 Verma S, Buchanan MR, Anderson TJ. Endothelial
2008;5:833–40. function testing as a biomarker of vascular disease.
71 Champion HC, Bivalacqua TJ, Hyman AL, Circulation 2003;108:2054–9.
Ignarro LJ, Hellstrom WJ, Kadowitz PJ. Gene 83 Virag R, Bouilly P, Frydman D. Is impotence an
transfer of endothelial nitric oxide synthase to the arterial disorder. Lancet 1985;1:181–4.
penis augments erectile responses in the aged rat. 84 Chiurla E, D’Amico R, Ratti C, Granata AR,
Proc Natl Acad Sci USA 1999;96:11648–52. Romagnoli R, Modena MG. Subclinical cornoray

J Sex Med 2009;6:2390–2404


atherosclerosis in patients with erectile dysfunc- ments of endothelial function and oxidative stress
tion. J Am Coll Cardiol 2005;46:1503–6. after daily dosing of Sildenafil in type 2 diabetic
85 Tee GB, Rasool AH, Halim AS, Rahman AR. men with erectile dysfunction. J Urol 2009;181:
Dependence of human forearm skin postocclusive 245–51.
reactive hyperemia on occlusion time. J Pharmacol 97 Eguchi M, Masuda H, Asahara T. Endothelial pro-
Toxicol Methods 2004;50:73–8. genitor cells for postnatal vasculogenesis. Clin Exp
86 Kevin JT, Mammen A, Mooney P, Alsheikh-Ali Nephrol 2007;11:18–25.
AA, Karas RH. Assesment of peripheral vascular 98 Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa
endothelium function in the ambulatory setting. M, Britten M, Kamper U, Dimmeler S, Zeiher
Vasc Med 2007;12:13–6. AM. Reduced number of circulating endothelial
87 Bonetti PO, Pumper GM, Higano ST, Holmes progenitor cells predicts future cardiovascular
DR Jr, Kuvin JT, Lerman A. Noninvasive identi- events: Proof of concept for the clinical importance
fication of patients with early coronary atheroscle- of endogenous vascular repair. Circulation 2005;
rosis by assessment of digital reactive hyperemia. 111:2981–7.
J Am Coll Cardiol 2004;44:2137–41. 99 Baumhäkel M, Werner N, Böhm M, Nickenig G.
88 Hamburg N, Keyes MJ, Larson MG, Vasan RS, Circulating endothelial progenitor cells correlate
Schnabel R, Pryde MM, Mitchell GF, Sheffy J, with erectile function in patients with coronary
Vita JA, Benjamin EJ. Cross-sectional relations of heart disease. Eur Heart J 2006;27:2184–8.
digital vascular function to cardiovascular risk 100 Foresta C, Caretta N, Lana A, Cabrelle A, Palù G,
factors in the Framingham heart study. Circulation Ferlin A. Circulating endothelial progenitor cells
2008;117:2467–74. in subjects with erectile dysfunction. Int J Impot
89 Billups KL, Kaiser DR, Kelly AS, Wetterling RA, Res 2005;17:288–90.
Tsai MY, Hanson N, Bank AJ. Relation of 101 Esposito K, Ciotola M, Maiorino MI, Giugliano F,
C-reactive protein and other cardiovascular risk Autorino R, De Sio M, Jannini E, Lenzi A,
factors to penile vascular disease in men with Giugliano D. Circulating CD34+ KDR+ endothe-
erectile dysfunction. Int J Impot Res 2003;15: lial progenitor cells correlate with erectile function
231–6. and endothelial function in overweight men. J Sex
90 El Melegy NT, Ali ME, Awad EM. Plasma levels Med 2009;6:107–14.
of endothelin-1, angiotensin II, nitric oxide and 102 Virag R. Flow dependent dilatation of the cavern-
prostaglandin E in the venous and cavernosal ous arteries. A potential test of penile NO content.
blood of patients with erectile dysfunction. BJU Int J Mal Vasc 2002;27:214–7.
2005;96:1079–86. 103 Virag R, Floresco J, Richard C. Impairment of
91 Bocchio M, Desideri G, Scarpelli P, Necozione S, shear stress-mediated vasodilatation of cavernous
Properzi G, Spartera C, Francavilla F, Ferri C, arteries in erectile dysfunction. Int J Impot Res
Francavilla S. Endothelial cell activation in men 2004;16:39–42.
with erectile dysfunction without cardiovascular 104 Galiano M, Costa C, Virag R. Penile endothelial
risk factors and overt vascular damage. J Urol function evaluation with the Penile NO release test
2004;171:1601–4. after radical prostatectomy. Clinical and therapeu-
92 Böger RH. Asymmetric dimethylarginine (ADMA) tic consequences. Annual French urological asso-
modulates endothelial function—therapeutic im- ciation (AFU) meeting 2008; Abstract 071.
plications. Vasc Med 2003;8:149–51. 105 Vardi Y, Dayna L, Apple B, Gruenwald I, Ofer Y,
93 Maas R, Wenske S, Zabel M, Ventura R, Schwed- Jacob G. Penile and systemic endothelial function
helm E, Steenpass A, Klemm H, Noldus J, Böger with and without erectile dysfunction. Eur Urol
RH. Elevation of asymmetrical dimethylarginine 2008; PMID: PMID: 18692305 [Epub ahead of
(ADMA) and coronary artery disease in men with print, Aug 7].
erectile dysfunction. Eur Urol 2005;48:1004–11. 106 Mazo E, Gamidov S, Anranovich S, Iremashvili V.
94 Juonala M, Vikari JS, Alfthan G, Marniemi J, Mah- Testing endothelial function of brachial and cav-
noman M, Taittonen L, Taittonen T, Raitakari ernous arteries in patients with erectile dysfunc-
OT. Brachial artery flow-mediated dilation and tion. J Sex Med 2006;3:323–30.
asymetrical dimethyl arginine in the cardiovascular 107 Moulier V, Mouras H, Pélégrini-Issac M, Glutron
risk in young Finns study. Circulation 2007; D, Rouxel R, Grandjean B, Bittoun J, Stoléru S.
116:1367–73. Neuroanatomical correlates of penile erection
95 Demir T, Cömlekci A, Demir O, Gülcü A, Calis- evoked by photographic stimuli in human males.
kan S, Argun L, Secil M, Yesil S, Esen A. A possible Neuroimage 2006;33:689–99.
new risk factor in diabetic patients with erectile 108 Aversa A, Caprio M, Rosano GM, Spera G. Endot-
dysfunction. J Diabetes Complications 2008;6: helial effects of drugs designed to treat erectile
395–9. dysfunction. Curr Pharm Des 2008;14:3768–78.
96 Burnett AL, Strong TD, Trock BJ, Jin L, Bivilac- 109 De Young LX, Domes T, Lim K, Carson J, Brock
qua TJ, Musicki B. Serum biomarkers measure- GB. Endothelial rehabilitation: The impact of

J Sex Med 2009;6:2390–2404


chronic PDE5 inhibitors on erectile function and administration and improvement of endothelial
protein alterations in cavernous tissue of diabetic function in men with erectile dysfunction: A pilot
rats. Eur Urol 2008;54:213–20. study. Int J Impot Res 2007;19:200–7.
110 Musicki B, Liu T, Strong T, Jin L, Laughlin MN, 113 Bocchio M, Pelliccione F, Passaquale G, Mihalca
Turk JR, Burnett AL. Low-fat diet and exercise R, Necozione S, Desideri G, Francavilla F, Ferri
preserve regulation and endothelial function in the C, Francavilla S. Inhibition of phosphodiesterase
penis of early atherosclerotic pigs: A molecular type 5 with tadalafil is associated to an improved
analysis. J Sex Med 2008;3:552–61. activity of circulating angiogenic cells in men with
111 Virag R, Galiano M, Floresco J, Hastert V. cardiovascular risk factors and erectile dysfunction.
Improvement of penile endothelial function with Atherosclerosis 2008;196:313–9.
Elliovir (association of arginine, superoxydismu- 114 Mazo EB, Gamidov ST, Tremashvili VV. Does the
tase and grape seeds extracts). Angeiologie 2008; clinical efficay of vardenafil correlates with the
60:13–9. effect on the endothelial function of cavernous
112 Aversa A, Greco E, Bruzziches R, Pili M, Rosano arteries. A pilot study. BJU Int 2006;98:1054–
G, Spera G. Relationship between chronic tadalafil 8.

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