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Wang S, Zhang A, Liu K, Pan Y, Kang J, Niu S, Song Y, Zhang Z, Li Y, Liu L, Liu X. A study of diabetes-induced erectile dysfunction treated with human umbilical cord mesenchymal stem cells. Andrologia 2022; 54:e14440. [PMID: 35415927 DOI: 10.1111/and.14440] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/22/2022] [Accepted: 04/03/2022] [Indexed: 12/12/2022] Open
Abstract
The present study aimed to assess the value of human umbilical cord mesenchymal stem cells (hUC-MSCs) for the treatment of diabetes-induced erectile dysfunction (DMED). We established a type 1 diabetes model through intra-abdominal streptozotocin injection. After 10 weeks, an apomorphine test was performed to screen the rats for erectile dysfunction (ED). The rats were divided into three groups: normal control group (n = 10), DMED group (n = 9) and DMED+hUC-MSC group (n = 9). After 4 weeks of hUC-MSC therapy, erectile function was evaluated by intracavernous pressure measurements, and penile tissue collagen and smooth muscle were examined by haematoxylin-eosin and Masson's trichrome staining. In addition, western blotting, immunohistochemistry and RT-PCR analysis of TLR4, VEGF and eNOS were performed. The results showed that hUC-MSC treatment restored erectile function (p < .05) and reversed the smooth muscle/collagen ratio changes of DMED rats (p < .05). Furthermore, hUC-MSC treatment inhibited the expression of TLR4 (p < .05) and enhanced VEGF and eNOS expression (p < .05). In conclusion, hUC-MSC treatment restored the erectile function of diabetic rats by inhibiting TLR4, improving corpora cavernosa fibrosis, and increasing VEGF and eNOS expression.
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Affiliation(s)
- Shangren Wang
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Aiqiao Zhang
- Department of Neonatology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,Department of Neonatology, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Kang Liu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yang Pan
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jiaqi Kang
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shuai Niu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuxuan Song
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhexin Zhang
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuezheng Li
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Li Liu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaoqiang Liu
- Department of Urology, Tianjin Medical University General Hospital, Tianjin, China
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Pakpahan C, Ibrahim R, William W, Faizah Z, Juniastuti J, Lusida MI, Oceandy D. Stem cell therapy and diabetic erectile dysfunction: A critical review. World J Stem Cells 2021; 13:1549-1563. [PMID: 34786157 PMCID: PMC8567456 DOI: 10.4252/wjsc.v13.i10.1549] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/04/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Erectile dysfunction (ED) has been identified as one of the most frequent chronic complications of diabetes mellitus (DM). The prevalence of ED is estimated to be about 67.4% in all DM cases worldwide. The pathophysiological process leading to ED involves endothelial, neurological, hormonal, and psychological factors. In DM, endothelial and neurological factors play a crucial role. Damages in the blood vessels and erectile tissue due to insulin resistance are the hallmark of ED in DM. The current treatments for ED include phosphodiesterase-5 inhibitors and penile prosthesis surgery. However, these treatments are limited in terms of just relieving the symptoms, but not resolving the cause of the problem. The use of stem cells for treating ED is currently being studied mostly in experimental animals. The stem cells used are derived from adipose tissue, bone, or human urine. Most of the studies observed an improvement in erectile quality in the experimental animals as well as an improvement in erectile tissue. However, research on stem cell therapy for ED in humans remains to be limited. Nevertheless, significant findings from studies using animal models indicate a potential use of stem cells in the treatment of ED.
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Affiliation(s)
- Cennikon Pakpahan
- Department of Biomedical Sciences, Universitas Airlangga, Surabaya 60132, Indonesia
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
| | - Raditya Ibrahim
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
| | - William William
- Andrology Program, Universitas Airlangga, Surabaya 60132, Indonesia
- Department of Medical Biology, School of Medicine and Health Sciences Atma Jaya Catholic University of Indonesia, Jakarta 14440, Indonesia
| | - Zakiyatul Faizah
- Department of Biomedical Sciences, Universitas Airlangga, Surabaya 60132, Indonesia
| | | | - Maria I Lusida
- Institute for Tropical Disease, Universitas Airlangga, Surabaya 60132, Indonesia
| | - Delvac Oceandy
- Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom
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Irdam GA, Febriyani, Rasyid N, Taher A. A systematic review of intracavernosal injection of mesenchymal stem cells for diabetic erectile dysfunction. MEDICAL JOURNAL OF INDONESIA 2021. [DOI: 10.13181/mji.oa.204475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
BACKGROUND As current erectile dysfunction (ED) treatments are limited, other treatment such as stem cells should be explored. Hence, this study aimed to review the sources, method of administration, and therapeutic effect of mesenchymal stem cells (MSCs) for diabetic ED treatment.
METHODS All relevant articles regarding the use of MSCs for diabetic ED were searched in PubMed and Google Scholar databases from December 15, 2019 to January 1, 2020 published in the past 10 years. The keywords were “mesenchymal stem cells” and “diabetic ED”. The selection and critical appraisal of the studies were discussed. Diabetic ED was evaluated for functional and structural outcome. Functional outcome in animal studies was assessed by intracavernosal pressure/mean arterial pressure (ICP/MAP) ratio, meanwhile the structural outcome was done microscopically. In human study, the assessments were done using international index of erectile function score (IIEF-5) to erection hardness score and penile Doppler ultrasonography.
RESULTS There were 10 animal studies and 3 human studies. The studies used MSCs from adipose (n = 6), bone marrow (n = 4), placenta (n = 1), umbilical cord (n = 1), and muscle tissue (n = 1). The MSCs were administrated through intracavernosal injection in all studies. In all animal studies, functional outcome was improved, shown in higher ICP/MAP ratio. Microscopically, there were an increase of cavernosal endothelial cells, vascular endothelial growth factor, nitric oxide synthase, and smooth muscle cells. In human studies, IIEF-5 and erection hardness score were improved. Peak systolic velocity was also higher.
CONCLUSIONS MSCs may be a promising therapy for diabetic ED; however, long-term safety concerns still need further investigations.
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Britt D, Blankstein U, Lenardis M, Millman A, Grober E, Krakowsky Y. Availability of platelet-rich plasma for treatment of erectile dysfunction and associated costs and efficacy: A review of current publications and Canadian data. Can Urol Assoc J 2020; 15:202-206. [PMID: 33212009 DOI: 10.5489/cuaj.6947] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Platelet-rich plasma (PRP) is an increasingly used unconventional treatment option for erectile dysfunction (ED). The validity of PRP as a potential treatment for ED has been proposed in limited human trials. Furthermore, the costs associated with PRP for ED treatment are not readily promoted to patients. The goal of this review was to determine the efficacy and costs of PRP based on currently available literature and Canadian data. METHODS A comprehensive literature review of available PRP studies and current published data pertaining to cost, availability, and provider clinics globally was conducted using the PubMed database. Physicians offering genital PRP in Canada were identified using internet searches and PRP provider directories. Physician qualifications, clinic locations, and cost information were obtained from provider websites and telephone calls to identified clinics. RESULTS Availability of PRP injections offered for treating ED is increasing globally. There are currently no peer-reviewed publications to substantiate anecdotal evidence pertaining to the efficacy of PRP as a viable treatment option for ED patients. Our results indicate 19 providers for PRP injections in Canada, costing on average $1777 CAD per injection. No providers were affiliated with academic institutions and providers varied in their area of clinical speciality and training. CONCLUSIONS To our knowledge, there is currently no research underway investigating the clinical efficacy of PRP for ED treatment despite its broad availability and significant cost. Patients should be informed of the lack of substantiated efficacy and safety data, as the reliability of PRP treatments requires further evaluation.
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Affiliation(s)
- Deron Britt
- University of Ottawa, Faculty of Medicine, Ottawa, ON, Canada
| | - Udi Blankstein
- Division of Urology, University of Toronto, Toronto, ON, Canada
| | | | | | - Ethan Grober
- Women's College Hospital, Division of Urology, University of Toronto, Toronto, ON, Canada
| | - Yonah Krakowsky
- Women's College Hospital, Division of Urology, University of Toronto, Toronto, ON, Canada
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Liu MC, Chang ML, Wang YC, Chen WH, Wu CC, Yeh SD. Revisiting the Regenerative Therapeutic Advances Towards Erectile Dysfunction. Cells 2020; 9:E1250. [PMID: 32438565 PMCID: PMC7290763 DOI: 10.3390/cells9051250] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/14/2020] [Accepted: 05/15/2020] [Indexed: 12/12/2022] Open
Abstract
Erectile dysfunction (ED) is an inability to attain or maintain adequate penile erection for successful vaginal intercourse, leading to sexual and relationship dissatisfaction. To combat ED, various surgical and non-surgical approaches have been developed in the past to restore erectile functions. These therapeutic interventions exhibit significant impact in providing relief to patients; however, due to their associated adverse effects and lack of long-term efficacy, newer modalities such as regenerative therapeutics have gained attention due to their safe and prolonged efficacy. Stem cells and platelet-derived biomaterials contained in platelet-rich plasma (PRP) are thriving as some of the major therapeutic regenerative agents. In recent years, various preclinical and clinical studies have evaluated the individual, as well as combined of stem cells and PRP to restore erectile function. Being rich in growth factors, chemokines, and angiogenic factors, both stem cells and PRP play a crucial role in regenerating nerve cells, myelination of axons, homing and migration of progenitor cells, and anti-fibrosis and anti-apoptosis of damaged cavernous nerve in corporal tissues. Further, platelet-derived biomaterials have been proven to be a biological supplement for enhancing the proliferative and differentiation potential of stem cells towards neurogenic fate. Therefore, this article comprehensively analyzes the progresses of these regenerative therapies for ED.
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Affiliation(s)
- Ming-Che Liu
- Department of Urology, Taipei Medical University Hospital, Taipei 11031, Taiwan; (M.-C.L.); (C.-C.W.)
- Clinical Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Graduate Institute of Clinical Medicine, school of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Meng-Lin Chang
- Department of Urology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 242, Taiwan;
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- Graduate Institute of Applied Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Ya-Chun Wang
- TCM Biotech International Corp., New Taipei City 22175, Taiwan; (Y.-C.W.); (W.-H.C.)
| | - Wei-Hung Chen
- TCM Biotech International Corp., New Taipei City 22175, Taiwan; (Y.-C.W.); (W.-H.C.)
| | - Chien-Chih Wu
- Department of Urology, Taipei Medical University Hospital, Taipei 11031, Taiwan; (M.-C.L.); (C.-C.W.)
- Department of Education and Humanities in Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Shauh-Der Yeh
- Department of Urology and Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Yang M, Sun JY, Ying CC, Wang Y, Guo YL. Adipose-derived stem cells modified by BDNF gene rescue erectile dysfunction after cavernous nerve injury. Neural Regen Res 2020; 15:120-127. [PMID: 31535660 PMCID: PMC6862402 DOI: 10.4103/1673-5374.264464] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cavernous nerve injury is the main cause of erectile dysfunction following radical prostatectomy. The recovery of erectile function following radical prostatectomy remains challenging. Our previous studies found that injecting adipose-derived stem cells (ADSCs) into the cavernosa could repair the damaged cavernous nerves, but the erectile function of the treated rats could not be restored to a normal level. We evaluated the efficacy of ADSCs infected with a lentiviral vector encoding rat brain-derived neurotrophic factor (lenti-rBDNF) in a rat model of cavernous nerve injury. The rats were equally and randomly divided into four groups. In the control group, bilateral cavernous nerves were isolated but not injured. In the bilateral cavernous nerve injury group, bilateral cavernous nerves were isolated and injured with a hemostat clamp for 2 minutes. In the ADSCGFP and ADSCrBDNF groups, after injury with a hemostat clamp for 2 minutes, rats were injected with ADSCs infected with lenti-GFP (1 × 106 in 20 μL) and lenti-rBDNF (1 × 106 in 20 μL), respectively. Erectile function was assessed 4 weeks after injury by measuring intracavernosal pressures. Then, penile tissues were collected for histological detection and western blot assay. Results demonstrated that compared with the bilateral cavernous nerve injury group, erectile function was significantly recovered in the ADSCGFP and ADSCrBDNF groups, and to a greater degree in the ADSCrBDNF group. Neuronal nitric oxide synthase content in the dorsal nerves and the ratio of smooth muscle/collagen were significantly higher in the ADSCrBDNF and ADSCGFP groups than in the bilateral cavernous nerve injury group. Neuronal nitric oxide synthase expression was obviously higher in the ADSCrBDNF group than in the ADSCGFP group. These findings confirm that intracavernous injection with ADSCs infected with lenti-rBDNF can effectively improve erectile dysfunction caused by cavernous nerve injury. This study was approved by the Medical Animal Care and Welfare Committee of Wuhan University, China (approval No. 2017-1638) on June 20, 2017.
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Affiliation(s)
- Mei Yang
- Department of Endocrinology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, Hubei Province, China
| | - Jiang-Yang Sun
- Department of Hepatobiliary Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Cheng-Cheng Ying
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yong Wang
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yong-Lian Guo
- Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Ding XG, Li SW, Zheng XM, Wang XH, Luo Y. Cavernous nerve reconstruction with autologous vein graft and platelet-derived growth factors. Asian J Androl 2018; 19:298-302. [PMID: 26952958 PMCID: PMC5427784 DOI: 10.4103/1008-682x.175780] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
In this study, we investigated the feasibility of using autologous vein graft and platelet-derived growth factors to bridge transected cavernous nerve in a rat model. A short defect in the bilateral cavernous nerve was created and repaired with vein graft from the right jugular vein or vein graft plus platelet-derived growth factors. The 32 rats were divided into four groups, namely Group 1 - no repair as a negative control, Group 2 - vein graft alone, Group 3 - vein graft plus platelet-derived growth factors, and Group 4 - sham operation as a positive control. We evaluated nerve regeneration and functional recovery using retrograde tracing study with FluoroGold, Toluidine blue staining of cavernous nerve, and the intracavernous pressure at 3 months. Three months after surgery, rich FluoroGold-positive cells were observed in the sham and vein graft plus platelet-derived growth factors group, but very few were found in the no repair group. The number of myelinated axons of regenerated cavernous nerve and intracavernous pressure were increased obviously in the two vein graft groups, especially in the vein graft plus platelet-derived growth factors group. These findings confirm the feasibility of using autologous vein as guides for cavernous nerve regeneration, and the regeneration can be further enhanced when the vein is filled with platelet-derived growth factors.
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Affiliation(s)
- Xie-Gang Ding
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Shi-Wen Li
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Xin-Min Zheng
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Xing-Huan Wang
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
| | - Yi Luo
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China
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8
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Lee YC, Huang SP, Tsai CC, Cheng KH, Juan YS, Wu WJ, Bao BY, Huang CN, Wang CJ, Liu CC. Associations of VEGF Gene Polymorphisms With Erectile Dysfunction and Related Risk Factors. J Sex Med 2017; 14:510-517. [DOI: 10.1016/j.jsxm.2017.02.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/27/2017] [Accepted: 02/08/2017] [Indexed: 01/08/2023]
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Abstract
The application of targeted temperature management has become common practice in the neurocritical care setting. It is important to recognize the pathophysiologic mechanisms by which temperature control impacts acute neurologic injury, as well as the clinical limitations to its application. Nonetheless, when utilizing temperature modulation, an organized approach is required in order to avoid complications and minimize side-effects. The most common clinically relevant complications are related to the impact of cooling on hemodynamics and electrolytes. In both instances, the rate of complications is often related to the depth and rate of cooling or rewarming. Shivering is the most common side-effect of hypothermia and is best managed by adequate monitoring and stepwise administration of medications specifically targeting the shivering response. Due to the impact cooling can have upon pharmacokinetics of commonly used sedatives and analgesics, there can be significant delays in the return of the neurologic examination. As a result, early prognostication posthypothermia should be avoided.
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Affiliation(s)
- N Badjatia
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
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10
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Kim JH, Lee HJ, Song YS. Mesenchymal stem cell-based gene therapy for erectile dysfunction. Int J Impot Res 2016; 28:81-7. [PMID: 26888355 DOI: 10.1038/ijir.2016.3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Revised: 10/17/2015] [Accepted: 11/23/2015] [Indexed: 12/12/2022]
Abstract
Despite the overwhelming success of PDE5 inhibitor (PDE5I), the demand for novel pharmacotherapeutic and surgical options for ED continues to rise owing to the increased proportion of elderly individuals in the population, in addition to the growing percentage of ED patients who do not respond to PDE5I. Surgical treatment of ED is associated with many complications, thus warranting the need for nonsurgical therapies. Moreover, none of the above-mentioned treatments essentially corrects, cures or prevents ED. Although gene therapy is a promising option, many challenges and obstacles such as local inflammatory response and random transgene expression, in addition to other safety issues, limit its use at the clinical level. The use of stem cell therapy alone also has many shortcomings. To overcome these inadequacies, many scientists and clinicians are investigating new gene and stem cell therapies.
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Affiliation(s)
- J H Kim
- Department of Urology, Soonchunhyang University Hospital, College of Medicine, Soonchunhyang University, Seoul, Korea
| | - H J Lee
- Biomedical Research Institute, Chung-Ang School of Medicine, Seoul, Korea
| | - Y S Song
- Department of Urology, Soonchunhyang University Hospital, College of Medicine, Soonchunhyang University, Seoul, Korea
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Lacchini R, Tanus-Santos JE. Pharmacogenetics of erectile dysfunction: navigating into uncharted waters. Pharmacogenomics 2015; 15:1519-38. [PMID: 25303302 DOI: 10.2217/pgs.14.110] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Sildenafil and other PDE-5 inhibitors have revolutionized erectile dysfunction (ED) treatment. However, a significant number of patients do not respond or present adverse reactions to these drugs. While genetic polymorphisms may underlie this phenomenon, very little research has been undertaken in this research field. Most of the current knowledge is based on sildenafil, thus almost completely ignoring other important pharmacological therapies. Currently, the most promising genes with pharmacogenetic implications in ED are related to the nitric oxide and cGMP pathway, although other genes are likely to affect the responsiveness to treatment of ED. Nevertheless, the small number of studies available opens the possibility of further exploring other genes and phenotypes related to ED. This article provides a comprehensive overview of the genes being tested for their pharmacogenetic relevance in the therapy of ED.
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Affiliation(s)
- Riccardo Lacchini
- Department of Psychiatric Nursing & Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
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12
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Hsu CH, Lin CL, Wang SE, Sheu SJ, Chien CT, Wu CH. Oral treatment with herbal formula B401 alleviates penile toxicity in aging mice with manganism. Clin Interv Aging 2015; 10:907-18. [PMID: 26064043 PMCID: PMC4455845 DOI: 10.2147/cia.s82026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The present study aims to elucidate the roles of nitric oxide synthase activity, oxidative stress, inflammation, and apoptosis in penile toxicity of aging mice associated with excess manganese (Mn) treatment and to investigate the effect of oral treatment with the herbal formula B401 in this respect. ICR strain mice were divided into two groups: the vehicle (sham group) and the B401 (50 mg/kg) group. The mice were orally treated for 5 days; then a high single dose of MnCl2 (100 mg/kg) was given by intraperitoneal injection to the mice. One day after MnCl2 treatment, corpora cavernosal tissues of both Mn-treated mice and their controls were simultaneously sampled to examine their immunohistochemical staining and Western blot analysis. Nitric oxide (NO) production, levels of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), expression levels of factors governing angiogenesis (vascular endothelial growth factor), oxidative stress (catalase, superoxide dismutase 2,4-hydroxynonenal), inflammation (tumor necrosis factor alpha), apoptosis (B-cell lymphoma 2 [Bcl-2], Bcl-2-associated X protein [Bax], cleaved poly(adenosine diphosphate-ribose) polymerase [c-PARP], cytochrome C, caspase-12, and caspase-3) were evaluated in penile corpus cavernosum of the mice. We found that penile toxicity in the mice was enhanced under excess Mn treatment through reduction of NOS activity and increase in oxidative stress, inflammation, and apoptosis in the penile cavernous tissue. Furthermore, the penile toxicity in mice with manganism was alleviated by oral B401 treatment through enhancement of both nitric oxide synthesis and angiogenesis, with simultaneous reduction of oxidative stress, inflammation, and apoptosis in penile corpus cavernosum. We suggest that the herbal formula B401 may serve as a potential dietotherapeutic supplement for penile toxicity or dysfunction in aging males.
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Affiliation(s)
- Chih-Hsiang Hsu
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Ching-Lung Lin
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Sheue-Er Wang
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | | | - Chiang-Ting Chien
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Chung-Hsin Wu
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
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13
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Aoun F, Peltier A, van Velthoven R. Penile rehabilitation after pelvic cancer surgery. ScientificWorldJournal 2015; 2015:876046. [PMID: 25785286 PMCID: PMC4345049 DOI: 10.1155/2015/876046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 01/16/2015] [Indexed: 01/19/2023] Open
Abstract
Erectile dysfunction is the most common complication after pelvic radical surgery. Rehabilitation programs are increasingly being used in clinical practice but there is no high level of evidence supporting its efficacy. The principle of early penile rehabilitation stems from animal studies showing early histological and molecular changes associated with penile corporal hypoxia after cavernous nerve injury. The concept of early penile rehabilitation was developed in late nineties with a subsequent number of clinical studies supporting early pharmacologic penile rehabilitation. These studies included all available phosphodiesterase type 5 inhibitors, intracavernosal injection and intraurethral use of prostaglandin E1 and to lesser extent vacuum erectile devices. However, these studies are of small number, difficult to interpret, and often with no control group. Furthermore, no studies have proven an in vivo derangement of endothelial or smooth muscle cell metabolism secondary to a prolonged flaccid state. The purpose of the present report is a synthetic overview of the literature in order to analyze the concept and the rationale of rehabilitation program of erectile dysfunction following radical pelvic surgery and the evidence of such programs in clinical practice. Emphasis will be placed on penile rehabilitation programs after radical cystoprostatectomy, radical prostatectomy, and rectal cancer treatment. Future perspectives are also analyzed.
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Affiliation(s)
- Fouad Aoun
- Department of Urology, Jules Bordet Institute, 1 Héger-Bordet Street, 1000 Brussels, Belgium
- Université Libre de Bruxelles, 50 Franklin Roosevelt Avenue, 1050 Brussels, Belgium
| | - Alexandre Peltier
- Department of Urology, Jules Bordet Institute, 1 Héger-Bordet Street, 1000 Brussels, Belgium
- Université Libre de Bruxelles, 50 Franklin Roosevelt Avenue, 1050 Brussels, Belgium
| | - Roland van Velthoven
- Department of Urology, Jules Bordet Institute, 1 Héger-Bordet Street, 1000 Brussels, Belgium
- Université Libre de Bruxelles, 50 Franklin Roosevelt Avenue, 1050 Brussels, Belgium
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14
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Ichim TE, Warbington T, Cristea O, Chin JL, Patel AN. Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction? J Transl Med 2013; 11:139. [PMID: 23758954 PMCID: PMC3718667 DOI: 10.1186/1479-5876-11-139] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 04/23/2013] [Indexed: 02/06/2023] Open
Abstract
While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.
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Affiliation(s)
- Thomas E Ichim
- Institute for Molecular Medicine, Huntington Beach, CA, USA.
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Ying C, Yang M, Zheng X, Hu W, Wang X. Effects of intracavernous injection of adipose-derived stem cells on cavernous nerve regeneration in a rat model. Cell Mol Neurobiol 2013; 33:233-40. [PMID: 23161147 PMCID: PMC11497875 DOI: 10.1007/s10571-012-9890-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Accepted: 11/03/2012] [Indexed: 12/19/2022]
Abstract
The aim of this study was to investigate effects of intracavernous injection of adipose-derived stem cells (ADSCs) on cavernous nerve (CN) regeneration and functional status in a nerve-crush rat model. Thirty Sprague-Dawley male rats were randomly divided into three equal groups: one group underwent sham operation, while two groups underwent bilateral CN crush. Crush-injury group was treated at the time of injury with intracavernous injection of ADSCs, or injured control group with no further intervention. Erectile function was assessed by CN electrostimulation after 3 months. Penile tissue and crushed nerves were collected for histology. Three months after surgery, in the group that underwent bilateral nerve crushing with no further intervention, the functional evaluation showed a lower mean maximal intracavernous pressure (ICP) and maximal ICP per mean arterial pressure (MAP) with CN stimulation than those in the sham group. In the group with an immediate intracavernous injection of ADSCs, the mean maximal ICP and maximal ICP/MAP were significantly higher than those in the injured control group. Histologically, the group with the intracavernous injection of ADSCs had more myelinated axons of CNs and more NADPH-diaphorase-positive nerve fibers than the injured control group but fewer than the sham group. Intracavernous injection of ADSCs treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum. These results show that the intracavernous injection of ADSCs to the site of CN-crush injury facilitates nerve regeneration and recovery of erectile function. Our research indicates that penile injection of ADSCs can improve recovery of erectile function in a rat model of neurogenic ED.
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Affiliation(s)
- Chengcheng Ying
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, 430071 China
| | - Mei Yang
- Department of Endocrinology, Puren Hospital, Wuhan University of Science and Technology, Wuhan, 430081 China
| | - Xinmin Zheng
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, 430071 China
| | - Wanli Hu
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, 430071 China
| | - Xinghuan Wang
- Department of Urology, Zhongnan Hospital, Wuhan University, Wuhan, 430071 China
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16
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Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJG. Endothelial Dysfunction in Erectile Dysfunction: Role of the Endothelium in Erectile Physiology and Disease. ACTA ACUST UNITED AC 2013; 24:S17-37. [PMID: 14581492 DOI: 10.1002/j.1939-4640.2003.tb02743.x] [Citation(s) in RCA: 183] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Trinity J Bivalacqua
- Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
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Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, Lin CS. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med 2012; 10:738-46. [PMID: 23253086 DOI: 10.1111/jsm.12024] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Introduction. Low-energy shockwave therapy (LESWT) has been shown to improve erectile function in patients suffering from diabetes mellitus (DM)-associated erectile dysfunction (ED). However, the underlying mechanism remains unknown. Aim. The aim of this study is to investigate whether LESWT can ameliorate DM-associated ED in a rat model and examine the associated changes in the erectile tissues. Methods. Newborn male rats were intraperitoneally injected with 5-ethynyl-2-deoxyuridine (EdU; 50 mg/kg) for the purpose of tracking endogenous mesenchymal stem cells (MSCs). Eight weeks later, eight of these rats were randomly chosen to serve as normal control (N group). The remaining rats were injected intraperitoneally with 60 mg/kg of streptozotocin (STZ) to induce DM. Eight of these rats were randomly chosen to serve as DM control (DM group), whereas another eight rats were subject to shockwave (SW) treatment (DM+SW group). Each rat in the DM+SW group received 300 shocks at energy level of 0.1 mJ/mm(2) and frequency of 120/minute. This procedure was repeated three times a week for 2 weeks. Another 2 weeks later, all 24 rats were evaluated for erectile function by intracavernous pressure (ICP) measurement. Afterward, their penile tissues were examined by histology. Main Outcome Measures. Erectile function was measured by ICP. Neuronal nitric oxide synthase (nNOS)-positive nerves and the endothelium were examined by immunofluorescence staining. Smooth muscle and MSCs were examined by phalloidin and EdU staining, respectively. Results. STZ treatment caused a significant decrease in erectile function and in the number of nNOS-positive nerves and in endothelial and smooth muscle contents. These DM-associated deficits were all partially but significantly reversed by LESWT. MSCs (EdU-positive cells) were significantly more numerous in DM+SW than in DM rats. Conclusion. LESWT can partially ameliorate DM-associated ED by promoting regeneration of nNOS-positive nerves, endothelium, and smooth muscle in the penis. These beneficial effects appear to be mediated by recruitment of endogenous MSCs. Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, and Lin C-S. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med 2013;10:738-746.
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Affiliation(s)
- Xuefeng Qiu
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143-0738, USA
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Wu C, Wu Y, Ho H, Chen K, Sheu M, Chiang H. The Neuroprotective Effect of Platelet‐rich Plasma on Erectile Function in Bilateral Cavernous Nerve Injury Rat Model. J Sex Med 2012; 9:2838-48. [DOI: 10.1111/j.1743-6109.2012.02881.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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VEGF genetic polymorphisms affect the responsiveness to sildenafil in clinical and postoperative erectile dysfunction. THE PHARMACOGENOMICS JOURNAL 2012; 13:437-42. [DOI: 10.1038/tpj.2012.39] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Revised: 07/23/2012] [Accepted: 08/20/2012] [Indexed: 11/08/2022]
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An G, Ji C, Wei Z, Chen H, Zhang J. The therapeutic role of VEGF-expressing muscle-derived stem cells in acute penile cavernosal injury. J Sex Med 2012; 9:1988-2000. [PMID: 22759755 DOI: 10.1111/j.1743-6109.2012.02827.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
INTRODUCTION Traumatic penile injury is one of the urological emergencies. Surgery and conservative management are major treatment methods but are always accompanied by many complications. AIM To investigate the feasibility of repairing cavernous tissues in acute rabbit penile cavernosal injury model with vascular endothelial growth factor (VEGF)-expressing muscle-derived stem cells (MDSCs). METHODS MDSCs were isolated and transfected with hVEGF165 lentiviral gene vector in vitro. The expression of VEGF was confirmed using enzyme-linked immunosorbent assay (ELISA), Western blot, and real-time polymerase chain reaction (PCR) analyses. After animal models were constructed, animals were randomly divided into four groups, which were administrated with MDSCs/VEGF, MDSCs/vector, MDSCs, and normal saline, respectively. A month later, magnetic resonance imaging (MRI) and intracavernosal pressures (ICP) were performed on the animals. Then penile tissues were harvested and assayed with Western blot and immunohistochemistry. MAIN OUTCOME MEASURES Real-time PCR, Western blot, ELISA, immunohistochemistry, MRI, and ICP were performed in our experiments. RESULTS The expression of VEGF significantly increased in the VEGF-expressing MDSCs group compared with those in the MDSCs/vector and MDSCs groups. VEGF protein expression in the injury sites of cavernous tissues were significantly higher in the MDSCs/VEGF group compared with those in other three groups. Immunohistochemical staining showed that α-smooth muscle actin-positive cells, von Willebrand factor-positive cells and capillary density markedly increased in the MDSCs/VEGF group. Animals receiving MDSCs/VEGF showed a significant improvement in cavernosal contractile function and structural repair. CONCLUSIONS The transplantation of VEGF-expressing MDSCs could repair the actuely injured cavernous tissue. We believed that it could be a novel therapeutic strategy for acute rabbit penile cavernosal injury.
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Affiliation(s)
- Geng An
- Department of Plastic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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21
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Yohendran J, Chauhan D. Erectile dysfunction following intravitreal bevacizumab. Middle East Afr J Ophthalmol 2011; 17:281-4. [PMID: 20844689 PMCID: PMC2934725 DOI: 10.4103/0974-9233.65497] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Despite initial concerns regarding systemic complications, the use of intravitreal antivascular endothelial growth factor (anti-VEGF) agents for ocular disease is rapidly expanding worldwide, in terms of both the number of patients injected and its indications. To our knowledge, there are no cases in the literature reporting erectile dysfunction following the use of intravitreal bevacizumab. We postulate an organic mechanism for impaired erectile function due to systemically absorbed intravitreal bevacizumab. We describe a case of erectile dysfunction following intravitreal bevacizumab administration. Color fundus photos, fluorescein angiogram and optical coherence tomography images are presented. A 40-year-old male underwent intravitreal bevacizumab therapy for macular edema secondary to a branch retinal vein occlusion. He subsequently developed transient erectile dysfunction after each of his two bevacizumab injections. His only comorbidity was mild hypertension. Erectile dysfunction may be a side effect of intravitreal bevacizumab. The erectile dysfunction could be organic and/or psychogenic in etiology.
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Affiliation(s)
- Jayshan Yohendran
- Vision Retinal Institute, 852 Whitehorse Road, Box Hill VIC 3128, Australia
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Liu G, Sun X, Dai Y, Zheng F, Wang D, Huang Y, Bian J, Deng C. Chronic administration of sildenafil modified the impaired VEGF system and improved the erectile function in rats with diabetic erectile dysfunction. J Sex Med 2011; 7:3868-78. [PMID: 20487237 DOI: 10.1111/j.1743-6109.2010.01844.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Men frequently develop diabetic erectile dysfunction (DMED), as a result of endothelial dysfunction. DMED patients often have reduced efficacy with phosphodiesterase type 5 inhibitors therapy. AIM To determine whether chronic sildenafil administration can modify the impaired vascular endothelial growth factor (VEGF) system and improve the erectile function in rats with diabetic erectile dysfunction. METHODS A group of Sprague Dawley rats (n = 30) with DMED were induced by intraperitoneal injection of streptozotocin (40 mg/kg) and screened by subcutaneous injection of Apomorphine (100 mg/kg). They were then exposed to either vehicle or sildenafil (prescribed in our hospital, 5 mg/kg and 10 mg/kg, respectively) for 10 weeks. An additional nondiabetic and age-matched control group (n = 10) was also allocated and given the routine diet for the same period. Assessments were performed to both groups at 36 hours after the last dose of sildenafil. Penile intracavernous pressure (ICP), mean arterial pressure (MAP), penile tissue morphology, immunohistologic analysis, and Western blot analysis of VEGF, VEGFR1, and eNOS were determined. MAIN OUTCOME MEASURE Functional, morphological, and proteomical changes on penile structures by the chronic Sildenafil (5 mg/kg and 10 mg/kg, respectively) administration were determined. RESULTS A significant increase of ICP, ICP/MAP ratio, and area under the curve were observed in the both groups treated by sildenafil (5 mg/kg and 10 mg/kg, respectively), compared with the DMED rats without receiving Sildenafil. Immunohistochemical staining of their penile tissue showed a decrease in VEGF, VEGFR1, and eNOS staining in the controlled group compared with an improvement in the chronic sildenafil administration group. Western blot analysis demonstrated exactly the same results. CONCLUSION We demonstrated that daily sildenafil administration can restore the impaired VEGF system in the penis of DMED rats and progressively improve both erectile function and endothelial function, suggesting a potential general mechanism of improved signaling through the VEGF/eNOS signaling cascade.
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Affiliation(s)
- Guihua Liu
- Department of Urology, First Affiliated Hospital of Sun Yet-Sen University, Guangzhou, China
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23
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Burnett AL, Goldstein I, Andersson KE, Argiolas A, Christ G, Park K, Xin ZC. Future sexual medicine physiological treatment targets. J Sex Med 2011; 7:3269-304. [PMID: 21029380 DOI: 10.1111/j.1743-6109.2010.02025.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
INTRODUCTION Sexual function in men and women incorporates physiologic processes and regulation of the central and peripheral nervous systems, the vascular system, and the endocrine system. There is need for state-of-the-art information as there is an evolving research understanding of the underlying molecular biological factors and mechanisms governing sexual physiologic functions. AIM To develop an evidence-based, state-of-the-art consensus report on the current knowledge of the major cellular and molecular targets of biologic systems responsible for sexual physiologic function. METHODS State-of-the-art knowledge representing the opinions of seven experts from four countries was developed in a consensus process over a 2-year period. MAIN OUTCOME MEASURES Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS Scientific investigation in this field is needed to increase knowledge and foster development of the future line of treatments for all forms of biological-based sexual dysfunction. This article addresses the current knowledge of the major cellular and molecular targets of biological systems responsible for sexual physiologic function. Future treatment targets include growth factor therapy, gene therapy, stem and cell-based therapies, and regenerative medicine. CONCLUSIONS Scientific discovery is critically important for developing new and increasingly effective treatments in sexual medicine. Broad physiologic directions should be vigorously explored and considered for future management of sexual disorders.
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Affiliation(s)
- Arthur L Burnett
- The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, MD, USA.
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24
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Labinskyy N, Hicks S, Grijalva J, Edwards J. The Contrary Impact Of Diabetes And Exercise On Endothelial Nitric Oxide Synthase Function. WEBMEDCENTRAL 2010; 1. [PMID: 27683619 DOI: 10.9754/journal.wmc.2010.00137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Zhang HY, Jin XB, Lue TF. Three important components in the regeneration of the cavernous nerve: brain-derived neurotrophic factor, vascular endothelial growth factor and the JAK/STAT signaling pathway. Asian J Androl 2010; 13:231-5. [PMID: 21170078 DOI: 10.1038/aja.2010.162] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Retroperitoneal operations, such as radical prostatectomy, often damage the cavernous nerve, resulting in a high incidence of erectile dysfunction. Although improved nerve-sparing techniques have reduced the incidence of nerve injury, and the administration of phosphodiesterase type 5 inhibitors has revolutionized the treatment of erectile dysfunction, this problem remains a considerable challenge. In recent years, scientists have focused on brain-derived neurotrophic factor and vascular endothelial growth factor in the treatment of cavernous nerve injury in rat models. Results showed that both compounds were capable of enhancing the regeneration of the cavernous nerve and that activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway played a major role in the process.
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Affiliation(s)
- Hai-Yang Zhang
- Minimally Invasive Urology Center, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
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26
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Gou X, He WY, Xiao MZ, Qiu M, Wang M, Deng YZ, Liu CD, Tang ZB, Li J, Chen Y. Transplantation of endothelial progenitor cells transfected with VEGF165 to restore erectile function in diabetic rats. Asian J Androl 2010; 13:332-8. [PMID: 21113173 DOI: 10.1038/aja.2010.116] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The present study investigated the effect of transplanting endothelial progenitor cells (EPCs) transfected with the vascular endothelial growth factor gene (VEGF165) into the corpora cavernosa of rats with diabetic erectile dysfunction (ED). A rat model of diabetic ED was constructed via intraperitoneal injection of streptozotocin. After streptozotocin treatment, pre-treated EPCs from each of three groups of rats were transplanted into their corpora cavernosa. Our results, following intracavernosal pressure (ICP) monitoring, showed that ICP increased significantly among rats in the trial group when compared to the results from rats in the blank-plasmid and control groups during basal conditions and electrical stimulation (P<0.01 for both comparisons). Histological examination revealed extensive neovascularisation in the corpora cavernosa of rats in the trial group. Fluorescence microscopy indicated that many of the transplanted EPCs in the trial group survived, differentiated into endothelial cells and integrated into the sites of neovascularisation. Based on the results of this study, we conclude that transplantation of VEGF165-transfected EPCs into the corpora cavernosa of rats with diabetic ED restores erectile function.
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Affiliation(s)
- Xin Gou
- Department of Urology, First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China.
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Lysiak JJ, Kavoussi PK, Ellati RT, Steers WD, Annex BH. Angiogenesis Therapy for the Treatment of Erectile Dysfunction. J Sex Med 2010; 7:2554-63. [DOI: 10.1111/j.1743-6109.2010.01830.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Huang YC, Ning H, Shindel AW, Fandel TM, Lin G, Harraz AM, Lue TF, Lin CS. The effect of intracavernous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model. J Sex Med 2010; 7:1391-400. [PMID: 20141586 DOI: 10.1111/j.1743-6109.2009.01697.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Hyperlipidemia has been associated with erectile dysfunction (ED) via damage to the cavernous endothelium and nerves. Adipose tissue-derived stem cells (ADSC) have been shown to differentiate into endothelial cells and secrete vasculotrophic and neurotrophic factors. AIM To assess whether ADSC have therapeutic effects on hyperlipidemia-associated ED. METHODS Twenty-eight male rats were induced to develop hyperlipidemia with a high-fat diet (hyperlipidemic rats, HR). Ten additional male rats were fed a normal diet to serve as controls (normal rats, NR). Five months later, all rats were subjected to ADSC isolation from paragonadal fat. The cells were cultured for 1 week, labeled with 5-ethynyl-2'-deoxyuridine (EdU), and then injected autologously into the corpus cavernosum of 18 HR. The remaining 10 HR rats were injected with phosphate buffered saline (PBS). At 2 and 14 days post-transplantation, four rats in the HR + ADSC group were sacrificed for tracking of the transplanted cells. At 28 days post-transplantation, all remaining rats were analyzed for serum biochemistry, erectile function, and penile histology. MAIN OUTCOME MEASURES Erectile function was assessed by intracavernous pressure (ICP) measurement during electrostimulation of the cavernous nerve. Cavernous nerves, endothelium, and smooth muscle were assessed by immunohistochemistry. RESULTS Serum total cholesterol and low-density lipoprotein levels were significantly higher in HR than in NR. High-density lipoprotein level was significantly lower in HR than in NR. Mean ICP/mean arterial pressure ratio was significantly lower in HR + PBS than in NR + PBS or HR + ADSC. Neuronal nitric oxide synthase (nNOS)-positive nerve fibers and endothelial cells were fewer in HR + PBS than in HR + ADSC. Smooth muscle content was significantly higher in both HR groups than in NR. CONCLUSIONS Hyperlipidemia is associated with abnormalities in both the nerves and endothelium. Treatment with ADSC ameliorates these adverse effects and holds promise as a potential new therapy for ED.
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Affiliation(s)
- Yun-Ching Huang
- Knuppe Molecular Urology Laboratory, Department of Urology, University of California, San Francisco, CA, USA
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29
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Nicolini A, Carpi A. Immune manipulation of advanced breast cancer: an interpretative model of the relationship between immune system and tumor cell biology. Med Res Rev 2009; 29:436-71. [PMID: 19105214 DOI: 10.1002/med.20143] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
This review summarizes some recent clinical immunological approaches with cytokines and/or antibodies for therapy of advanced breast cancer. It considers the recent advances in genetics and molecular tumor biology related to impaired immunosurveillance involving cytokines and growth factors to explain clinical results. Evasion of the host immune attack might be induced by the following groups of mechanisms: (a) tumor dependent (genomic instability, HLA class I antigen abnormalities, upregulation of fetal type nonclassical HLA class I molecules, epitope immunodominance, apoptosis inhibition by defective death receptor signaling, apoptosis of activated T cells, tumor cannibalism and constitutive activation of signal transducer, and activator of transcription-3 (Stat 3) and nuclear factor-kappaB (NF-kappaB) signaling); (b) host dependent (CD4+CD25+ regulatory T cells (T reg), CD4+ T cells anergy, Th2 antitumor immunity diversion and myeloid suppressor cells); (c) tumor and host dependent (lack of co-stimulation molecules, immunosuppressive cytokines (vascular endothelial growth factor (VEGF), interleukin (IL)-10, prostaglandin (PG)E2, transforming growth factor (TGF)-beta)). Cytokines and growth factors are involved in virtually all three types of mechanisms. These mechanisms are integrated with the current knowledge of tumor growth and inhibited apoptosis primarily mediated by cytokines and growth factors to propose an interpretation of the relationships among tumor cells, tumor stroma, and tumor-infiltrating lymphocytes. Tumor growth, defective immunorecognition and immunosuppression are the three principal effects considered responsible for immune evasion.
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Affiliation(s)
- Andrea Nicolini
- Department of Internal Medicine, University of Pisa, Pisa, Italy.
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30
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The effect of platelet-rich plasma on cavernous nerve regeneration in a rat model. Asian J Androl 2009; 11:215-21. [PMID: 19151738 DOI: 10.1038/aja.2008.37] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The aim of this study was to investigate the effect of platelet-rich plasma (PRP) on cavernous nerve (CN) regeneration and functional status in a nerve-crush rat model. Twenty-four Sprague-Dawley male rats were randomly divided into three equal groups: eight had a sham operation, eight underwent bilateral nerve crushing with no further intervention and eight underwent bilateral nerve crushing with an immediate application of PRP on the site of injury. Erectile function was assessed by CN electrostimulation at 3 months and nerve regeneration was assessed by toluidine blue staining of CN and nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining of penile tissue. Three months after surgery, in the group that underwent bilateral nerve crushing with no further intervention, the functional evaluation showed a lower mean maximal intracavernous pressure (ICP) and maximal ICP per mean arterial pressure (MAP) with CN stimulation than those in the sham group. In the group with an immediate application of PRP, the mean maximal ICP and maximal ICP/MAP were significantly higher than those in the injured control group. Histologically, the group with the application of PRP had more myelinated axons of CNs and more NADPH-diaphorase-positive nerve fibres than the injured control group but fewer than the sham group. These results show that the application of PRP to the site of CN-crush injury facilitates nerve regeneration and recovery of erectile function. Our research indicates that clinical application of PRP has potential repairing effect on CN and peripheral nerves.
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31
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Azadzoi KM, Siroky M. Oxidative Stress and Molecular Reactions in Arteriogenic Erectile Dysfunction. Chonnam Med J 2009. [DOI: 10.4068/cmj.2009.45.1.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Kazem M Azadzoi
- Department of Urology and Pathology, VA Boston Healthcare System and Boston University School of Medicine, Massachusetts, USA
| | - Mike Siroky
- Department of Urology and Pathology, VA Boston Healthcare System and Boston University School of Medicine, Massachusetts, USA
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32
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Strong TD, Gebska MA, Burnett AL, Champion HC, Bivalacqua TJ. Endothelium-specific gene and stem cell-based therapy for erectile dysfunction. Asian J Androl 2008; 10:14-22. [DOI: 10.1111/j.1745-7262.2008.00362.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Mo KI, Lee HI, Lee KS. Changes in Corpus Cavernosum after Partial Bladder Outlet Obstruction in Rat. Korean J Urol 2008. [DOI: 10.4111/kju.2008.49.2.160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Affiliation(s)
- Kyo Ik Mo
- Department of Urology, College of Medicine, Dongguk University, Gyeongju, Korea
| | - Hyung Il Lee
- Department of Urology, College of Medicine, Dongguk University, Gyeongju, Korea
| | - Kyung Seop Lee
- Department of Urology, College of Medicine, Dongguk University, Gyeongju, Korea
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34
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Neuromodulatory drugs for the radical prostatectomy patient: Current and future applications. CURRENT SEXUAL HEALTH REPORTS 2006. [DOI: 10.1007/s11930-006-0014-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Schwarz ER, Rastogi S, Kapur V, Sulemanjee N, Rodriguez JJ. Erectile Dysfunction in Heart Failure Patients. J Am Coll Cardiol 2006; 48:1111-9. [PMID: 16978992 DOI: 10.1016/j.jacc.2006.05.052] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2006] [Revised: 04/26/2006] [Accepted: 05/01/2006] [Indexed: 11/17/2022]
Abstract
Chronic heart failure (HF) and erectile dysfunction (ED) are 2 highly prevalent disorders that frequently occur concomitantly. Coronary artery disease, HF, and ED share several common risk factors, including diabetes mellitus, hypertension, smoking, and dyslipidemia. Additionally, the distinct physiologic sequelae of HF create unique organic and psychologic factors contributing to ED in this patient population. Standard HF therapy with beta-receptor blockers, digoxin and thiazide diuretics may worsen sexual dysfunction owing to medication side effects. This may, in turn, lead to noncompliance in misguided efforts to retain satisfactory sexual activity, with secondary worsening of cardiac capacity. This review describes the unique aspects of ED in the HF population.
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Affiliation(s)
- Ernst R Schwarz
- Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
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Abstract
Pelvic surgeries are among the most common causes of organic sexual dysfunction in men and women. The impact of nerve-sparing surgery on potency has been well documented in radical prostatectomy. However, its impact on potency needs to be evaluated in other pelvic surgeries. Sexual dysfunction is highly prevalent even after multiple technical advances in the field of oncological surgeries. The prevalence varies from 8 to 82%, depending on the type of pelvic surgery. In females, sexual dysfunction has not been evaluated adequately using validated questionnaires. However, in subspecialized circles, treatment for female sexual dysfunction is becoming routine. Currently, physicians have several options for the treatment of erectile dysfunction (ED) in men. Since the introduction of oral PDE-5 inhibitors, oral therapy has become the first-line treatment option for ED, irrespective of etiology. Currently available treatment options for the female sexual dysfunction include estrogens, androgens, phosphodiesterase inhibitors, and dopamine receptor antagonists. Initial reports regarding the role of early rehabilitation are encouraging and may become the part of routine practice in the management of ED after pelvic surgery. In this article, we summarize the sexual dysfunction following pelvic surgeries and their management.
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Affiliation(s)
- C Zippe
- Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
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37
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Rastogi S, Rodriguez JJ, Kapur V, Schwarz ER. Why do patients with heart failure suffer from erectile dysfunction? A critical review and suggestions on how to approach this problem. Int J Impot Res 2006; 17 Suppl 1:S25-36. [PMID: 16391540 DOI: 10.1038/sj.ijir.3901426] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chronic heart failure (HF) is an increasingly common cardiovascular disorder. The goal of health-care providers is to optimize quality of life in this population, including sexual health. Up to 75% of patients with HF report erectile dysfunction (ED). As HF is a condition with distinct physiologic sequelae, some unique organic and psychological factors contributing to ED in this patient population have been identified, along with risk factors common to the development of coronary artery disease, HF and ED. This review describes contributing factors to ED in the setting of HF and highlights treatment considerations for this distinct patient population.
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Affiliation(s)
- S Rastogi
- Department of Internal Medicine, Division of Cardiology, The University of Texas Medical Branch (UTMB), Galveston, 77555, USA
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Jin L, Foss CE, Zhao X, Mills TM, Wang MH, McCluskey LP, Yaddanapud GSS, Falck JR, Imig JD, Webb RC. Cytochrome P450 epoxygenases provide a novel mechanism for penile erection. FASEB J 2006; 20:539-41. [PMID: 16415108 DOI: 10.1096/fj.05-4341fje] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Erectile dysfunction (ED) is estimated to affect more than 30 million American men and 152 million men worldwide. Therapeutic agents targeting the nitric oxide/cyclic GMP signaling pathway have successfully treated patients with ED; however, the efficacies of these treatments are significantly lower in specific populations such as patients with diabetes. The goal of this study was to discover and identify new endothelium-derived relaxing factors involved in the regulation of erectile function, providing alternative therapeutic targets for treatment of ED. Immunoblotting results showed that protein expressions of epoxygenases from cytochrome P450 (CYP)2B, 2C and 2J subfamilies, as well as NADPH CYP reductase were present in rat corpora cavernosa, which was confirmed by immunohistochemical analysis. Furthermore, CYP2C was localized in cavernosal endothelial cells using double immunolabeling. CYP epoxygenase activity was analyzed by reverse-phase high-pressure liquid chromatography; and the results showed that 11,12- epoxyeicosatrienoic acid (EET) was the major product metabolized by CYP epoxygenases in rat corpora cavernosa. Inhibition of EETs function by injection of an EETs antagonist into rat penis significantly decreased intracavernosal pressure-induced by electrical stimulation of the major pelvic ganglion in vivo. In conclusion, our results suggest that EETs, produced by CYP epoxygenases, in penile endothelial cells serve as vasodilators. Inhibition of this pathway attenuated erectile function, suggesting that EETs are required for normal erection.
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Affiliation(s)
- Liming Jin
- Department of Physiology,Medical College of Georgia, Augusta, Georgia, USA.
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39
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Affiliation(s)
- Kazem M Azadzoi
- Urology Research, VA Boston Healthcare System and Boston University Medical School, Boston, MA 02130, USA.
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Liu WJ, Xin ZC, Xin H, Yuan YM, Tian L, Guo YL. Effects of icariin on erectile function and expression of nitric oxide synthase isoforms in castrated rats. Asian J Androl 2005; 7:381-8. [PMID: 16281085 DOI: 10.1111/j.1745-7262.2005.00066.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
AIM To investigate the effect of icariin on erectile function and the expression of nitric oxide synthase (NOS) isoforms in castrated rats. METHODS Thirty-two adult male Wistar rats were randomly divided into one sham-operated group (A) and three castrated groups (B, C and D). One week after surgery, rats were treated with normal saline (groups A and B) or oral icariin (1 mg/[kg.day] for group C and 5 mg/[kg.day] for group D) for 4 weeks. One week after treatment, the erectile function of the rats was assessed by measuring intracavernosal pressure (ICP) during electrostimulation of the cavernosal nerve. The serum testosterone (ST) levels, the percent of smooth muscle (PSM) in trabecular tissue, and the expression of mRNA and proteins of neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and phosphodiesterase V (PDE5) in corpus cavernosum (CC) were also evaluated. RESULTS ICP, PSM, ST and the expression of nNOS, iNOS, eNOS and PDE5 were significantly decreased in group B compared with those in group A (P 0.01). However, ICP, PSM and the expression of nNOS and iNOS were increased in groups C and D compared with those in group B (P 0.05). Changes in ST and the expression of eNOS and PDE5 were not significant (P 0.05) in groups C and D compared with those in group B. CONCLUSION Oral treatment with icariin ( 98.6 % purity) for 4 weeks potentially improves erectile function. This effect is correlated with an increase in PSM and the expression of certain NOS in the CC of castrated rats. These results suggest that icariin may have a therapeutic effect on erectile dysfunction.
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Affiliation(s)
- Wu-Jiang Liu
- Andrology Center of Peking University First Hospital, Beijing 100009, China
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Mancini A, Milardi D, Bianchi A, Summaria V, De Marinis L. Increased estradiol levels in venous occlusive disorder: a possible functional mechanism of venous leakage. Int J Impot Res 2005; 17:239-42. [PMID: 15578040 DOI: 10.1038/sj.ijir.3901287] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Venous insufficiency of the corpora cavernosa is the second most common cause of erectile dysfunction (ED). A functional insufficiency of the venous system has been hypothesised, but the cause is still unclear. To evaluate a possible endocrine mechanism, we have studied hormone profile in a group of nine patients with pure venous-leakage (VL) compared with a control group of 15 patients with ED of different origin. Prolactin, testosterone and gonadotropin levels did not differ among the two groups, while estradiol (E2) plasma concentration was significantly higher in VL patients compared to controls. Our data support the hypothesis that the steroid environment, in particular estradiol level, can influence venous vascular tone (via VEGF or NO), thus affecting venous leakage dysfunction. This point can explain a possible link between the high estradiol levels and a functional insufficiency of the venous system in ED.
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Affiliation(s)
- A Mancini
- Medical Pathology, Endocrinology, Catholic University, Rome, Italy.
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Burchardt M, Burchardt T, Anastasiadis AG, Buttyan R, de la Taille A, Shabsigh A, Frank J, Shabsigh R. Application of angiogenic factors for therapy of erectile dysfunction: Protein and DNA transfer of VEGF 165 into the rat penis. Urology 2005; 66:665-70. [PMID: 16140112 DOI: 10.1016/j.urology.2005.03.058] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2004] [Revised: 03/03/2005] [Accepted: 03/23/2005] [Indexed: 10/25/2022]
Abstract
OBJECTIVES To establish a laboratory animal model for vascular endothelial growth factor (VEGF) transfer in the rat penis to invent a curative therapy for erectile dysfunction (ED). Vascular insufficiency is a common pathomechanism of ED. Previous investigations have shown neovascularization of ischemic organs after gene transfer of VEGF. METHODS For VEGF-protein transfer, osmotic pumps were connected to the renal arteries of rats. The pumps were filled with human VEGF 165 protein (n = 20) or sterile saline (n = 20). After 28 days, a VEGF serum immunoassay was performed to document successful delivery. For VEGF-DNA transfer, liposome complexes containing VEGF 165 expression vectors were injected into rat corpora cavernosa. After immunostaining, computerized image analysis was performed to quantify the percentage of area (within the corpora cavernosa) covered by smooth muscle or endothelial cells. RESULTS The immunoassay of the VEGF-protein transfer showed a 10-fold greater VEGF concentration in the serum of rats carrying VEGF pumps than in the control group. In the VEGF-DNA transfer, the penes transfected with VEGF 165 vectors showed a 283-bp polymerase chain reaction product according to specific primers for human VEGF. Although statistical trends were measured in the VEGF protein-treated group, no statistically significant difference in smooth muscle or endothelial cell content was found between the control and VEGF-treated rats. CONCLUSIONS Our findings have established proof of principle for successful delivery of VEGF protein and VEGF-DNA transfer in the rat penis. This study was a prelude to attempt to manipulate genetically expression of angiogenic factors in insufficient erectile tissue as a curative therapy for ED.
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Affiliation(s)
- Martin Burchardt
- Department of Urology, Medizinische Hochschule Hannover, Hannover, Germany
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Chen KC, Minor TX, Rahman NU, Ho HC, Nunes L, Lue TF. The additive erectile recovery effect of brain-derived neurotrophic factor combined with vascular endothelial growth factor in a rat model of neurogenic impotence. BJU Int 2005; 95:1077-80. [PMID: 15839936 DOI: 10.1111/j.1464-410x.2005.05470.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To test the hypothesis that combined intracavernosal injection with vascular endothelial growth factor (VEGF) with adeno-associated virus-mediated brain-derived neurotrophic factor (AAV-BDNF) synergistically facilitates the neural regeneration and erectile function after cavernosal nerve injury. MATERIALS AND METHODS Forty Sprague-Dawley male rats were randomly divided into five equal groups: eight had a sham operation while 32 had bilateral cavernosal nerve freezing followed by an immediate intracavernosal injection with either phosphate-buffered saline (PBS), VEGF, AAV-BDNF, or AAV-BDNF + VEGF. Erectile function was assessed by cavernosal nerve electrostimulation at 3 months, and samples of the major pelvic ganglia and penile tissue were evaluated histologically. RESULTS In this animal model of impotence from nerve injury, the recovery of erectile function was greatest in those receiving AAV-BDNF + VEGF; the mean (sd) maximal intracavernosal pressure in this group was 87.2 (20.78) cmH2O, compared with 37.3 (11.39) for VEGF alone and 49.8 (29.58) for AAV-BDNF alone. No erectile dysfunction was identified in the sham group, with a pressure of 100.7 (22.70) cmH2O, while all treatment groups significantly outperformed the PBS (control) group, at 29.3 (13.52) cmH2O. Furthermore, all animals receiving monotherapy or combined treatment had more NADPH-diaphorase-positive nerve fibres than controls but less than in the sham group. CONCLUSION Bilateral cavernosal nerve freezing causes erectile dysfunction with accompanying neurological changes. Intracavernosal injection with either VEGF or AAV-BDNF alone enhances nerve regeneration, with combined therapy (VEGF and AAV-BDNF) promoting neural and erectile recovery additively.
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Affiliation(s)
- Kuo-Chiang Chen
- Department of Urology, University of California San Francisco, San Francisco, CA, USA
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De Young L, Bella A, Howard J, Brock G. Arteriogenic Erectile Dysfunction Alters Protein Expression within the Cavernosal Tissue in an Animal Model. J Sex Med 2005; 2:199-206. [PMID: 16422887 DOI: 10.1111/j.1743-6109.2005.20229.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Erectile dysfunction (ED) is a highly prevalent and often untreated condition. It may be a marker of underlying chronic illness and negatively impacts quality of life. Penile arterial insufficiency, frequently found in association with hypertension, dyslipidemia, diabetes mellitus, pelvic irradiation, trauma, and smoking, is the most common cause of ED. AIM This study was designed to measure the effect of penile hypoperfusion-induced alteration and injury on erectile tissue at the cellular and protein level. METHODS Eighteen 4-month-old male Sprague Dawley rats were placed into three groups (n = 6): sham surgery, unilateral internal iliac artery ligation (UIIAL), and bilateral internal iliac artery ligation (BIIAL). MAIN OUTCOME MEASURE Erectile function was assessed 4 weeks following arterial ligation surgery as measured by a rise in intracavernosal pressure induced by cavernosal nerve stimulation. Penile tissue alterations were characterized by immunohistochemistry, protein content measured by western blot, and "global" protein expression profile carried out by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) ProteinChip technology. RESULTS Significantly lower intracavernous pressures were demonstrated in animals subjected to UIIAL surgery, which correlated to the extent of artery ligation. The intensity and quantity of immunohistochemical staining for neuronal nitric oxide synthase, endothelial cell integrity, smooth muscle cell alpha-actin, and vascular endothelial growth factor (VEGF) receptor flk1 were decreased in the BIIAL group compared to sham controls. SELDI-TOF-MS analysis revealed changes in molecular expression of a approximately 6,560 Da protein relative to a 7,720 Da protein (peak ratio = 1.34 +/- 0.3, BIIAL; 0.36 +/- 0.1 controls, P < 0.05). CONCLUSIONS In this report, an animal model of vascular penile insufficiency demonstrates altered protein expression associated with cavernosal tissue injury and reduced erectile function. Although the clinical significance of these observations is currently undefined, this model may allow greater insight into the complex biologic changes associated with arteriogenic ED in man.
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Affiliation(s)
- Ling De Young
- Division of Urology, Department of Surgery, The University of Western Ontario, London, Ontario, Canada
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Bach MHM, Sadoun E, Reed MJ. Defects in activation of nitric oxide synthases occur during delayed angiogenesis in aging. Mech Ageing Dev 2004; 126:467-73. [PMID: 15722105 DOI: 10.1016/j.mad.2004.10.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2004] [Revised: 08/16/2004] [Accepted: 10/11/2004] [Indexed: 11/28/2022]
Abstract
Angiogenesis, the formation of new vessels from pre-existing vasculature, is impaired in aging. This is due, in part, to a lack of regulatory molecules such as nitric oxide (NO). We wished to test the hypothesis that there are deficits in the pathways that mediate NO production during angiogenesis (as defined by fibrovascular invasion into a polyvinyl alcohol (PVA) sponge implant), in aged mice in comparison to young mice. Sponges were implanted subcutaneously in young (6-8 months old, n=11) and aged (23-25 months old, n=13) mice and sampled at 14 and 19 days. Sections from the implants were stained with antibodies against vascular endothelial growth factor receptor 2 (VEGFR-2), Akt, phosphorylated Akt (p-Akt), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), inducible NOS (iNOS), and 3-nitrotyrosine (3-NT, a marker for nitrosylated proteins). Expression of VEGFR-2 was similar in the sponges of young and aged mice. Moreover, there were no significant differences in levels of Akt or its phosphorylated form in sponges from young and aged mice at 14 and 19 d. In marked contrast, levels of eNOS, p-eNOS and iNOS were significantly decreased in sponges from aged mice relative to young mice (p<0.02 for eNOS, p-eNOS and <0.01 for iNOS between young and aged mice). Concomitantly, there was diminished expression of 3-NT in the sponges from aged mice (p<0.05). Our data indicate that defects in the activation of nitric oxide synthases result in decreased NO production in aged tissues relative to young tissues. We propose that the subsequent lack of NO contributes to impaired angiogenesis in aging.
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Affiliation(s)
- Mary H M Bach
- Department of Medicine, Division of Gerontology and Geriatric Medicine, Harborview Medical Center Research and Training Building, School of Medicine, University of Washington, Box 359755, 325 9th Ave, Seattle, WA 98104-2499, USA
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Abstract
PURPOSE OF REVIEW The existence of three phosphodiesterase 5 inhibitors has resulted in an increase in the marketing of the drugs. This has led to a shift in focus from scientifically rigorous endpoints such as efficacy and adverse event profiles to patient preference. RECENT FINDINGS Although no consensus currently exists as to the correct methodology for preference studies, some basic guidelines should be adhered to, including: (1) the double-blinding of drug administration; (2) non-biased drug administration instructions; (3) an adequately conducted crossover study; (4) comparison of equivalent doses; (5) standardized preference assessment; (6) declaration of patient demographics; and (7) rigorous statistical analysis. These factors are discussed in the light of the three published preference studies. SUMMARY In the final analysis, it is unclear to this author how preference studies impact upon clinician decision-making when confronted by a patient with erectile dysfunction.
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Affiliation(s)
- John P Mulhall
- Department of Urology, Weill Medical College of Cornell University, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10021, USA.
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Park K, Ahn KY, Kim MK, Lee SE, Kang TW, Ryu SB. Intracavernosal Injection of Vascular Endothelial Growth Factor Improves Erectile Function in Aged Rats. Eur Urol 2004; 46:403-7. [PMID: 15306114 DOI: 10.1016/j.eururo.2004.04.032] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2004] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To investigate whether intracavernosal injection of vascular endothelial growth factor (VEGF) can restore erectile function in the aging rat. MATERIALS AND METHODS Ten young (4-5 months) and 30 old (24 months) Sprague-Dawley male rats were used. The old rats were divided into 3 groups: vehicle-only (phosphate buffered saline plus 0.1% bovine serum albumin; n = 10), VEGF 1 microg/kg (n = 10), and VEGF 10 microg/kg (n = 10). At 2 and 4 weeks after treatment, erectile function and histology were evaluated by hemodynamic study, histomorphometric analysis, and immunohistochemistry. RESULTS After 4 weeks of treatment, the ratio of peak intracavernosal pressure to systemic arterial blood pressure in response to neurostimulation was significantly higher in both the VEGF 1 microg/kg (79.9 +/- 7.7%) and the VEGF 10 microg/kg group (76.8 +/- 5.8%) compared to the vehicle-only group (63.1 +/- 8.5%; p < 0.05). The percentage of cavernosal smooth muscle was significantly higher in the VEGF 10 microg/kg group (16.1 +/- 1.4%) compared to the vehicle-only group (12.8 +/- 2.2%; p = 0.047). VEGF treatment in old rats increased e-NOS and VEGF expression in both treatment groups. CONCLUSION Intracavernosal injection of VEGF appears to restore smooth muscle integrity and improve erectile function in aged rats.
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Affiliation(s)
- Kwangsung Park
- Department of Urology, Chonnam National University Medical School, 8 Hakdong, Donggu, Gwangju 501-757, Republic of Korea.
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Musicki B, Palese MA, Crone JK, Burnett AL. Phosphorylated Endothelial Nitric Oxide Synthase Mediates Vascular Endothelial Growth Factor-Induced Penile Erection1. Biol Reprod 2004; 70:282-9. [PMID: 14522830 DOI: 10.1095/biolreprod.103.021113] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The objective of the present study was to evaluate whether vascular endothelial growth factor (VEGF)-induced penile erection is mediated by activation of endothelial nitric oxide synthase (eNOS) through its phosphorylation. We assessed the role of constitutively activated eNOS in VEGF-induced penile erection using wild-type (WT) and eNOS-knockout (eNOS(-/-)) mice with and without vasculogenic erectile dysfunction. Adult WT and eNOS(-/-) mice were subjected to sham operation or bilateral castration to induce vasculogenic erectile dysfunction. At the time of surgery, animals were injected intracavernosally with a replication-deficient adenovirus expressing human VEGF145 (10(9) particle units) or with empty virus (Ad.Null). After 7 days, erectile function was assessed in response to cavernous nerve electrical stimulation. Total and phosphorylated protein kinase B (Akt) as well as total and phosphorylated eNOS were quantitatively assessed in mice penes using Western immunoblot and immunohistochemistry. In intact WT mice, VEGF145 significantly increased erectile responses, and in WT mice after castration, it completely recovered penile erection. However, VEGF145 failed to increase erectile responses in intact eNOS(-/-) mice and only partially recovered erectile function in castrated eNOS(-/-) mice. In addition, VEGF145 significantly increased phosphorylation of eNOS at Serine 1177 by approximately 2-fold in penes of both intact and castrated WT mice. The data provide a molecular explanation for VEGF stimulatory effect on penile erection, which involves phosphorylated eNOS (Serine 1177) mediation.
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Affiliation(s)
- Biljana Musicki
- Department of Urology, The Johns Hopkins Hospital, Baltimore, Maryland 21287, USA.
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Wu G, Mannam AP, Wu J, Kirbis S, Shie JL, Chen C, Laham RJ, Sellke FW, Li J. Hypoxia induces myocyte-dependent COX-2 regulation in endothelial cells: role of VEGF. Am J Physiol Heart Circ Physiol 2003; 285:H2420-9. [PMID: 12881220 DOI: 10.1152/ajpheart.00187.2003] [Citation(s) in RCA: 85] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
There is increasing evidence that cyclooxygenase (COX)-2 possess both angiogenic and cardioprotective properties. We examined the effects of hypoxic cardiac myocytes (H9c2 cells) on COX-2 expression in human umbilical vein endothelial cells (HUVECs) to determine the pathway involved in COX-2 regulation. The medium from hypoxic (<1% O2) cardiac myocytes (HMCM) or normoxic cardiac myocytes (21% O2) was added to HUVEC cultures. HMCM induced a transient increase of COX-2 mRNA expression at 1 and 3 h without affecting the COX-1 mRNA level. A similar effect also observed in HMCM from cultured primary cardiac myocytes (rat neonatal cardiac myocytes). The increased COX-2 mRNA was associated with a time-dependent increase in COX-2 protein expression. COX-2 was significantly induced by VEGF (4.86 +/- 1.03-fold) and IL-1beta (3.93 +/- 0.89-fold) and slightly increased by TNF-alpha but not by FGF2, IGF-1, or PDGFs. Analysis of proteins secreted in HMCM showed increased levels of VEGF but not IL-1 beta or TNF-alpha. The HMCM-induced COX-2 expression was inhibited by the addition of an anti-VEGF neutralizing antibody. VEGF induced endothelial cell COX-2 expression by both increasing COX-2 transcription and prolonging the COX-2 mRNA half-life. Furthermore, staurosporine, a nonselective PKC inhibitor, prevented the induction of VEGF by hypoxia. Both a selective PKC-alpha and -beta inhibitor and an inducible nitric oxide synthase (NOS) inhibitor decreased the induction of COX-2 by HMCM and VEGF. Finally, HMCM-induced upregulation of COX-2 was accompanied by upregulation of PGI2 and PGE2. These results suggest that VEGF is one of the principal factors produced by hypoxic myocytes that is responsible for the induction of endothelial cell COX-2 expression. This process likely involves both PKC and NOS pathways. Our findings have important implications regarding the cardiac protection of COX-2 in ischemic heart disease.
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Affiliation(s)
- Guifu Wu
- Angiogenesis Research Center, Division of Cardiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, USA
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Hsieh PS, Bochinski DJ, Lin GT, Nunes L, Lin CS, Lue TF. The effect of vascular endothelial growth factor and brain-derived neurotrophic factor on cavernosal nerve regeneration in a nerve-crush rat model. BJU Int 2003; 92:470-5. [PMID: 12930443 DOI: 10.1046/j.1464-410x.2003.04373.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To test the hypothesis that an intracavernosal injection with brain-derived neurotrophin factor (BDNF) and vascular endothelial growth factor (VEGF) can facilitate nerve regeneration and recovery of erectile function after cavernosal nerve injury. MATERIALS AND METHODS The study included 25 Sprague-Dawley rats; four had a sham operation, seven bilateral nerve crushing with no further intervention, and 14 bilateral nerve crushing with either an immediate (seven) or delayed for 1 month (seven) intracavernosal injection with BDNF+VEGF. Erectile function was assessed by cavernosal nerve electrostimulation at 3 months, and neural regeneration by NADPH-diaphorase staining and tyrosine hydroxylase (TH) staining of penile tissue and major pelvic ganglia (MPG). RESULTS After nerve crushing, the functional evaluation at 3 months showed a lower mean (SD) intracavernosal pressure (ICP) with cavernosal nerve stimulation, at 33.9 (15.3) cmH2O, than in the sham group, at 107.8 (18.1) cmH2O. With an immediate injection with BDNF+VEGF the ICP was significantly higher than in the controls, at 67.8 (38.5) cmH2O. Even delayed injection with BDNF+VEGF improved the ICP, to 78.0 (21.8) cmH2O. Histological analysis of specimens stained for NADPH and TH showed a significant change in the morphology of terminal branches of the cavernosal and dorsal nerves, and the staining quality of the neurones in the MPG. The number of positively stained nerve fibres tended to revert to normal after treatment with BDNF+VEGF. CONCLUSION An intracavernosal injection with BDNF+VEGF appears to both prevent degeneration and facilitate regeneration of neurones containing neuronal nitric oxide synthase in the MPG, dorsal nerve and intracavernosal tissue. Therefore it might have therapeutic potential for enhancing the recovery of erectile function after radical pelvic surgery.
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Affiliation(s)
- P-S Hsieh
- Department of Urology, University of California, San Francisco, CA 94143, USA
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