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V O L U M E 5 2 · S U P P L . 1 T O N o . 2 · J U N E 2 0 1 0 CIRCULATING ENDOTHELIAL PROGENITOR CELLS
AND ERECTILE DYSFUNCTION: POSSIBILITY
OF NUTRITIONAL INTERVENTION?
T. E. ICHIM, Z. ZHONG, N. A. MIKIROVA, J. A. JACKSON, R. HUNNINGHAKE, E. MANSILLA, G. MARÍN, L. NÚÑEZ, A. N. PATEL, N. ANGLE, M. P. MURPHY, C. A. DASANU, D. T. ALEXANDRESCU, V. BOGIN, N. H. RIORDAN, PANMINERVA MED 2010;52(Suppl. 1 to No. 1):1-6 Circulating endothelial progenitor cells and erectile dysfunction:
possibility of nutritional intervention?
T. E. ICHIM 1*, Z. ZHONG 2*, N. A. MIKIROVA 3, J. A. JACKSON 4, R. HUNNINGHAKE 4, E. MANSILLA 5, G. MARÍN 5, L. NÚÑEZ 5, A. N. PATEL 6, N. ANGLE 7, M. P. MURPHY 8, C. A. DASANU 9, D. T. ALEXANDRESCU 10, V. BOGIN 11, N. H. RIORDAN 1, 12 To provide an overview of molecular and cellular processes
1Department of Urology, Medistem Inc involved in erectile dysfunction (ED) with emphasis on circu-
lating endothelial progenitor cells (EPC) and discuss possible
2The Second Xiangya Hospital of Central South University nutraceutical means of intervention. A review of literature on
Pubmed related to EPC and ED was conducted. Patients with
3Bio-Communications Research Institute ED appear to possess a reduced number of circulating EPC,
which is associated with poor endothelial function possibly as
4The Center for the Improvement of Human Functioning a result of underlying low-grade inflammation. Several studies
International, Wichita, Kansas, USA support the possibility of improving erectile function by inhi-
bition of inflammation as well as administration of various
6Department of Cardiothoracic Surgery, University of Utah stem cell types. One particularly interesting approach is
nutraceutical supplementation to increase circulating EPC, as
7Dept Vascular and Endovascular Surgery demonstrated in the product Stem-Kine. Interventions aimed
University of California San Diego, CA, USA at increasing circulating EPC may have potential in treatment
of vascular ED.
Indiana University School of Medicine, IN, USA Saint Francis Hospital and Medical Center EY WORDS: Endothelial progenitor cell - Erectile dysfunction -
10Georgetown Dermatology, Washington, DC, USA 11Chromos Pharma Services, Longview, WA, USA 12Aidan Products, Chandler, AZ, USA Erectile dysfunction (ED) is characterized by the lack of ability to achieve and maintain penile erec- tion for intercourse. It is estimated that 10-30 millionAmericans suffer from this condition and that 50-85%of cases are associated with conditions that affect theendothelium such as hypertension, diabetes, cardio-vascular disease, and dyslipidemia.1 Currently ED is patients are unresponsive to therapy or do not tolerate treated by oral inhibitors of phosphodiesterase-5 (silde- adverse effects associated with treatment.
nafil [Viagra, Revatio], tadalafil [Cialis]and vardenafil In addition, PDE5 inhibitors are known to possess [Levitra]), which are considered the standard of care a variety of systemic effects in numerous organ sys- for first-line treatment. Unfortunately, 30-40% of tems; therefore, the long- term effects of PDE5 inhi-bition are still uncertain. In fact, in 1998, the US Foodand Drug Administration published a report on 130 *These authors contributed equally to the paper.
confirmed deaths among men who received prescrip-tions for sildenafil citrate, in which causes of death Corresponding author: T. E Ichim, Chief Executive Officer, Medistem included arrythmias, sudden cardiac death and hypoten- Inc, 9255 Towne Centre Drive, Suite 450, San Diego, CA 92121, USA. E-mail: [email protected] Biology of erections
dysfunction occurs include oxidative stress in the formof the oxygen-free radical superoxide, which both The penis is comprised of three erectile bodies: the enhances degradation of NO (by direct conversion to corpora cavernosa, which consists of 2 parallel bodies, peroxynitrite), as well as by decrease of its produc- and underneath, wedged in between, the corpus spon- tion.5 Uncontrolled glucose levels, as found in dia- giosum, which contains the urethra. These three erec- betics, are a cause of advanced glycation end prod- tile bodies are heavily vascularized and contain a large ucts, which activate several inflammatory mechanisms proportion of smooth muscle cells. Erection is caused that directly or indirectly are adverse to endothelial by neurologically-induced relaxation of smooth mus- function.6 These glycation end products can inacti- cle cells in the erectile bodies, which allows influx vate NO directly as well as induce an increased pro- and accumulation of blood into the balloon-like sacs duction of superoxide, which also inhibits NO.
between the smooth muscle cells called sinusoids. As Additionally, glycation end products directly suppress blood accumulates, the outflow of blood is prevented synthesis of endothelial nitric oxide synthase (eNOS) by pressure from the tunica albuginea against the venous plexus, thus causing trapping of the blood, The primary effector of the molecular mechanisms allowing erection to occur. The process of blood accu- described above seems to be endothelial dysfunction.
mulation due to venous trapping is termed the veno- Montorsi et al. put forth the “Artery Size Hypothesis,” occlusive mechanism. Thus the main contributions to in which it was proposed that in comparison to larger maintaining an erection are arterial blood entry and vessels, smaller arteries, such as the pudendal arteries its venous trapping in the cavernous bodies. supplying blood to the penile structures, are more like- The relaxation of the smooth muscles around the ly to be affected by artherosclerotic and other forms of arteries is caused by parasympathetic nervous activa- endothelial damage. Accordingly, the argument is tion, which induces an increase in nitric oxide (NO) made that initiation of vascular disease is first identi- production by nonadrenergic, noncholinergic nerves, fied in many cases as ED, which subsequently pro- as well as endothelium which lines the penile arteries gresses to more advanced diseases. The authors make and cavernosal sinusoids. Accumulation of NO increas- 4 points supporting this hypothesis, namely: a) ED es production of cyclic guanosine monophosphate and coronary artery disease should be considered as (cGMP) through activation of the enzyme guanylyl two different manifestations of the same disease cyclase. cGMP acts as a second messenger which leads process; b) Prevalence of occult coronary artery disease to decreased calcium uptake into the cavernous andsmooth muscle cells, thus causing relaxation and hence in ED should be low; c) Prevalence of ED in patients erection.3 Since phosphodiesterase (PDE)-5 is involved with coronary artery disease should be high; and d) in the breakdown of cGMP, the inhibition of PDE-5 has Coronary artery disease should occur subsequently to been chosen as a pharmacological goal of medica- tions such as Viagra (sildenafil), Cialis (tadalafil) and Examining some studies that have addressed this Levitra (vardenafil). One of the first responses to dete- possibility, Min et al assessed 221 patients who were rioration in vascular disease is erectile function, pri- referred to undergo stress myocardial perfusion sin- marily due to abnormal endothelial and smooth mus- gle-photon, emission-computed tomography for car- cle responses. Accordingly, stem cell therapy may be diovascular concerns. In addition to the normal test- particularly promising in addressing this aspect, which ing procedure, the patient erectile function was quan- tified by the IIEF questionnaire. Patients with ED(54.8%) had a higher level of coronary heart disease incomparison to patients without ED (43.0% vs 17.0%, Vascular ED
respectively). Specifically, in comparison to patientswithout ED, ED patients had LVEF lower than 50% Given the complexity of the erectile process, it is (24.0% vs 11.0%), shorter exercise time (8.0 vs 10.1 not surprising that ED is multifactorial, with the main minutes) and lower Duke treadmill score (4.4 vs 8.4; cause, some studies citing up to 85%, being vascular; P<0.001). The role of ED as an independent predictor however ,endocrinological and neurological aspects of severe coronary heart disease was identified using also play a role.4 Specific means by which endothelial multivariate analysis (odds ratio, 2.50; 95% confidence interval, 1.24-5.04; P = 0.01).8 In another study, 12 the injury, which subsided to basal levels within 48-72 men with ED (IIEF-5 questionnaire score </=18) and hours.12 Another study examined post-infarct increas- 12 age-matched controls (IIEF-5 questionnaire score es in 26 patients, 10 stable angina controls, and 17 >/=21) were assessed for coronary flow velocity reserve healthy volunteers. An increase in circulating EPC by Doppler in the left anterior descending artery, before correlating with circulating VEGF was observed in and during adenosine infusion. Flow velocity reserve was significantly reduced in subjects with erectile dys- Direct support for the involvement of circulating function: 2.36 versus 3.19; P=0.024. Using multivari- EPC in healing of endothelium comes from animal ate analysis, adjusting for age, tobacco use, systolic studies using bone marrow transplant chimeras to iden- blood pressure, heart rate and body mass index, ED tify the origin of EPC. For example, Shi et al used was the only significant predictor of reduced coronary canine bone marrow transplants to demonstrate that flow velocity reserve, P=0.016.9 Correlation between when biocompatible grafts are exposed to circulation Framingham cardiovascular risk score and ED showed of the recipient dog, endothelialization occurred pri- that subjects in the heart disease risk cohort with mod- marily of donor-origin cells.14 In situations of arterial erate/severe ED (IIEF5 5-16) had a 65% increase in damage induced by wire injury, administration of relative risk for developing CHD within 10 yrs com- labeled EPC resulted in reduced neointimal forma- pared to those without ED (IIEF5 22-25).10 Thus it tion in a rabbit model, with accumulation of the labeled appears that ample support exists for ED being one of cells at the site of injury.15 It is believed that injured the primary manifestations of atherosclerosis.
endothelium secretes chemotactic signals such asMCP-1, which are responsible, at least in part, forselective attraction of EPC to the area of injury. Circulating endothelial progenitor cells
Instead of administering EPC, another interesting as rejuvenators of the vasculature
method of evoking healing through EPC is by stimu-lating their release from the bone marrow. G-CSF is a For several decades the bone marrow was studied pri- cytokine conventionally used for mobilization of marily as a source of hematopoietic stem cells, giving hematopoietic stem cells during transplantation; how- rise to the practice of bone marrow transplantation.
ever, it is also a known mobilizer of EPC. In an elegant More recently, studies have described bone marrow study it was demonstrated that induction of mobiliza- as containing cells capable of inducing healing in a tion by these means causes re-endothelialization of variety of non-hematopoietic conditions ranging from injured arteries, as well as functional recovery.16 liver failure to heart failure to peripheral arterial dis-ease. Although initially the concept was proposed thatbone marrow cells have “transdifferentiation” abili- Patients with ED have lower circulating EPC
ty, recent controversy surrounding this has led to thenotion that at least some of the non-hematopoietic As discussed above, one of the first targets of ath- effects of bone marrow administration are due to its erosclerotic disease is the penile vasculature.7 In gen- high content of endothelial progenitor cells. In 1997 eral, atherosclerotic disease is correlated with decreased Ashara et al. reported isolation of “circulating endothe- levels of circulating EPC. One study assessed patients lial progenitor cells” (EPC) from human and animal without cardiovascular disease that had varying scores on the Framingham risk questionnaire. A correlation The concept that the bone marrow produces a basal between higher risk scores and low EPC numbers was number of circulating EPC which act as “repair cells” found.17 Another study assessed the preclinical ather- for the peripheral vasculature was suggested by several osclerosis marker of carotid intima-media thickness lines of reasoning. The first was that in situations of (IMT) measured by ultrasound. The investigators found hypoxia, an increase in peripheral circulation of these a correlation between IMT and low levels of CD34+, cells can be observed. Ashara et al. first reported this KDR+ circulating EPC. Thus, given the hypothesis in animal models of limb ischemia.11 In a clinical study that ED is caused in many cases by atherosclerotic examining vascular trauma induced by burn (8 patients) disease, it should not be surprising that several studies and coronary artery bypass grafting (7 patients), a 50- have found patients with ED as having suppressed fold increase in circulating EPC occurred hours after Foresta et al. reported a lower number of cells capa- mine whether green tea administration altered cir- ble of forming CFU-E in circulation of men with ED culating EPC.25 Consumption of green tea daily for as compared with healthy controls. Their rationale 2 weeks resulted in an increase in circulating EPC, as was based on previous reports of cardiovascular disease well as improvement in endothelial function as mea- affecting the penile circulation first, and given that sured by the flow mediated dilation assay (FMD).
cardiovascular disease correlates with lower EPC, they In the specific case of ED, administration of the sought to verify if ED was an early manifestation of antioxidant vitamin alpha-tocophenol resulted in cardiovascular disease.18 A subsequent study of 119 IIEF improvement in a pilot group of patients resis- patients with coronary artery disease found that almost 60% had ED. Presence of ED correlated with known Thus it appears that in ED a low grade, underlying cardiovascular risk factors such as age, hypertension, inflammation, associated with markers such as CRP, reduced left ventricular ejection fraction (LVEF) and TNF-alpha, as well as oxidative stress, are associated diabetes. Importantly, ED correlated with reduction with reduction in EPC numbers and possibly causative in circulating EPC.19 A similar correlation was found of pathology. In order to investigate the link between in a study comparing 30 healthy overweight men with EPC and actual reversion of ED, we will discuss some 30 overweight men suffering from ED. Severity of studies in which administration of exogenous EPC or ED according to the IIEF score correlated with lower heterogeneous cell populations containing EPC were Inflammation causes lower numbers
Reversing endothelial dysfunction with EPC
of EPC in ED
The bone marrow is recognized as a major source Chronic inflammation has been associated with ED.
of EPC. Suggestive of the angiogenic potential of For example a study of 137 men with ED found sig- bone marrow was an early clinical study by Tateishi- nificant association between the levels of the inflam- Yuyama et al., in which 22 patients with bilateral matory marker C-reactive protein (CRP) and severity critical limb ischemia were treated intramuscularly of penile vascular disease as measured by penile with autologous bone marrow mononuclear cells in Doppler.21 In obese men, presence of ED was also randomly chosen legs, with control leg receiving associated with increased CRP-levels.22 Oxidative peripheral blood-derived mononuclear cells.27 stress is a known component in numerous inflamma- Improvement in the treated legs was observed in tory conditions. In ED, salivary 8-hydroxy-2’- terms of ankle brachial index, pain-free walking deoxyguanosine, a known marker of oxidative stress, and ulcer healing. One of the primary characteris- has been shown to correlate with severity of dysfunc- tics of endothelial dysfunction is reduction in the tion.23 Thus it appears that underlying chronic inflam- flow-mediated dilation assay. In an attempt to induce mation associated with atherosclerotic disease has a neo-angiogenesis through stimulation of circulat- negative effect on circulating EPC, which may account ing EPC numbers, mobilization of bone marrow for impaired endothelial repair and poor vascular func- progenitors was performed by a 2-week adminis- tion associated with ED. Supporting the inflammato- tration of GM-CSF in 45 patients with peripheral ry cause of EPC decrease are studies in which anti- arterial disease.28 At 12 weeks not only was improve- inflammatory agents partially or fully restore EPC ment in exercise capacity noted (as compared to numbers similar to healthy controls. For example, pre-treatment levels), but also systemic augmenta- Grisar et al. demonstrated in 28 patients with rheuma- tion of the flow-mediated dilation assay was report- toid arthritis that a 7-day course of TNF-alpha block- ed. These data suggest the possibility that adminis- ade resulted in restoration of circulating EPC to values tration of cells containing EPC, such as bone mar- comparable to healthy age-matched controls.24 row, as well as mobilization of endogenous bone Given the known component of oxidative stress marrow EPC may be useful in repairing/improving on inflammation, as well as the direct anti-inflam- endothelial function. Unfortunately autologous bone matory role of components in green tea, an investi- marrow therapy and mobilization by agents such as gation was conducted in 20 young smokers to deter- GM-CSF is cost-prohibitive and has a possibility of undue pain to the patient. In the case of autolo- time a means of assessing efficacy of an intervention gous bone marrow, the need to perform iliac crest before physical symptomology is observed. Non-inva- extraction to collect sufficient cell numbers is dif- sive approaches to augmenting circulating EPC such ficult to perform in patients that numerous times as administration of nutritional supplements offer a have a variety of comorbidity conditions. The use of new area of intervention for patients resistant to PDE5 cytokine-based mobilization, if used chronically, can lead to splenomegaly, bone marrow hyperplasia,and other adverse effects. References
Nutritional modulation of EPC
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Mobilization of EPC using nutritional-based 2. Shinlapawittayatorn K, Chattipakor S, Chattipakorn N. Effect of silde- approaches is particularly enticing. In a recent publi- nafil citrate on the cardiovascular system. Braz J Med Biol Res2005;38:1303-11.
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the bacterium, Lactobacillus fermentum. Extract of Oxygen free radicals and the penis. Expert Opin Pharmacother2002;3:889-97.
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root of astragalus are added prior to the fermentation Advanced glycation end-product cross-link breakers. A novel approa- process. While more studies are necessary to investi- ch to cardiovascular pathologies related to the aging process. Am JHypertens 2004;17:23S-30S.
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circulating progenitor levels in a physiological manner Erectile dysfunction in healthy subjects predicts reduced coronary without the adverse effects of agents such as G-CSF flow velocity reserve. Int J Cardiol 2006;112(2):166-70. Epub 2005Nov 4.
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