title: Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse.
abstract: OBJECTIVE
  Patients with diabetic erectile dysfunction often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. We examined the effectiveness of the potent angiopoietin-1 (Ang1) variant, cartilage oligomeric matrix protein (COMP)-Ang1, in promoting cavernous endothelial regeneration and restoring erectile function in diabetic animals.
  
  
  METHODS
  Four groups of mice were used: controls; streptozotocin (STZ)-induced diabetic mice; STZ-induced diabetic mice treated with repeated intracavernous injections of PBS; and STZ-induced diabetic mice treated with COMP-Ang1 protein (days -3 and 0). Two and 4 weeks after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested for histologic examinations, Western blot analysis, and cGMP quantification. We also performed a vascular permeability test.
  
  
  RESULTS
  Local delivery of the COMP-Ang1 protein significantly increased cavernous endothelial proliferation, endothelial nitric oxide (NO) synthase (NOS) phosphorylation, and cGMP expression compared with that in the untreated or PBS-treated STZ-induced diabetic group. The changes in the group that received COMP-Ang1 restored erectile function up to 4 weeks after treatment. Endothelial protective effects, such as marked decreases in the expression of p47(phox) and inducible NOS, in the generation of superoxide anion and nitrotyrosine, and in the number of apoptotic cells in the corpus cavernosum tissue, were noted in COMP-Ang1-treated STZ-induced diabetic mice. An intracavernous injection of COMP-Ang1 completely restored endothelial cell-cell junction proteins and decreased cavernous endothelial permeability. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished by the NOS inhibitor, N-nitro-L-arginine methyl ester, but not by the NADPH oxidase inhibitor, apocynin.
  
  
  CONCLUSIONS
  These findings support the concept of cavernous endothelial regeneration by use of the recombinant Ang1 protein as a curative therapy for diabetic erectile dysfunction.
authors.affiliation: National Research Laboratory of Regenerative Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: Jin
authors.forename: Woo Jean
authors.initials: WJ
authors.lastname: Kim
authors.forename: Jae Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Shuguang
authors.initials: S
authors.lastname: Piao
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Choi
authors.forename: Munkhbayar
authors.initials: M
authors.lastname: Tumurbaatar
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Shin
authors.forename: Guo Nan
authors.initials: GN
authors.lastname: Yin
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Ji-Kan
authors.initials: JK
authors.lastname: Ryu
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Suh
mesh_terms: D000704:Analysis of Variance; D042683:Angiopoietin-1 / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D007150:Immunohistochemistry; D018783:Impotence, Vasculogenic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010413:Penis / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
chemical_list: D042683:Angiopoietin-1; C515576:COMP-Ang1 fusion protein; D011993:Recombinant Fusion Proteins; D052250:Nitric Oxide Synthase Type III