title: Effectiveness of Intracavernous Delivery of Recombinant Human Hepatocyte Growth Factor on Erectile Function in the Streptozotocin-Induced Diabetic Mouse.
abstract: Diabetic erectile dysfunction is a disease mostly of vascular origin and men with diabetic erectile dysfunction respond poorly to oral phosphodiesterase-5 inhibitors. Hepatocyte growth factor (HGF) is a pleiotropic factor that plays an essential role in the regulation of cell proliferation, survival, and angiogenesis.
  
  
  
  To determine the effectiveness of recombinant human (rh)-HGF in restoring erectile function in diabetic mice.
  
  
  
  Four groups of mice were used: control non-diabetic mice and streptozotocin-induced diabetic mice receiving two successive intracavernous injections of phosphate buffered saline (days -3 and 0), a single intracavernous injection of rh-HGF (day 0), or two successive intracavernous injections of rh-HGF (days -3 and 0). We also examined the effect of rh-HGF in primary cultured mouse cavernous endothelial cells and in major pelvic ganglion culture in vitro, which was incubated under a normal-glucose (5 mmol/L) or a high-glucose (30 mmol/L) condition.
  
  
  
  Two weeks after treatment, we measured erectile function by electrical stimulation of the cavernous nerve and the penis was harvested for histologic studies.
  
  
  
  Repeated intracavernous injections of rh-HGF protein induced significant restoration of erectile function in diabetic mice (89-100% of control values), whereas a single intracavernous injection of rh-HGF protein elicited modest improvement. Rh-HGF significantly induced phosphorylation of its receptor c-Met, increased the content of endothelial cells and smooth muscle cells, and decreased the generation of reactive oxygen species (superoxide anion and peroxynitrite) and extravasation of oxidized low-density lipoprotein in diabetic mice. Under the high-glucose condition, rh-HGF protein also promoted tube formation in mouse cavernous endothelial cells and enhanced neurite sprouting in major pelvic ganglion culture in vitro.
  
  
  
  The dual angiogenic and neurotrophic effects of HGF could open a new avenue through which diabetic erectile dysfunction can be treated.
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea; Epigenetics Drug Discovery Unit, Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Suehiro-cho, Yokohama, Japan.
authors: Nando Dulal
authors: ND
authors: Das
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Guo Nan
authors: GN
authors: Yin
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Min Ji
authors: MJ
authors: Choi
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Kang-Moon
authors: KM
authors: Song
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Jin-Mi
authors: JM
authors: Park
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Anita
authors: A
authors: Limanjaya
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Kalyan
authors: K
authors: Ghatak
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Nguyen Nhat
authors: NN
authors: Minh
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Jiyeon
authors: J
authors: Ock
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Soo-Hwan
authors: SH
authors: Park
authors: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Ho Min
authors: HM
authors: Kim
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
authors: Ji-Kan
authors: JK
authors: Ryu
authors: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea. Electronic address: rjk0929@inha.ac.kr.
authors: Jun-Kyu
authors: JK
authors: Suh
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004727:Endothelium / Q000378:metabolism; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D015552:Injections, Intralesional; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000098:blood supply; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000502:physiology; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration / Q000502:physiology
chemical_list: D008077:Lipoproteins, LDL; D058986:Phosphodiesterase 5 Inhibitors; D011994:Recombinant Proteins; C099252:oxidized low density lipoprotein; D017228:Hepatocyte Growth Factor; D052250:Nitric Oxide Synthase Type III
keywords: Angiogenesis; Diabetes Mellitus; Erectile Dysfunction; Hepatocyte Growth Factor; Neural Regeneration