title: Designed angiopoietin-1 variant, COMP-angiopoietin-1, rescues erectile function through healthy cavernous angiogenesis in a hypercholesterolemic mouse.
abstract: Despite the advent of oral phosphodiesterase-5 inhibitors, curative treatment for erectile dysfunction (ED) remains unavailable. Recently, the link between ED and cardiovascular disease was unveiled and the main etiology of ED was found to be vasculogenic. Therefore, neovascularization is a promising strategy for curing ED. Angiopoietin-1 (Ang1) is an angiogenic growth factor that promotes the generation of stable and functional vasculature. Here, we demonstrate that local delivery of the soluble, stable, and potent Ang1 variant, COMP-Ang1 gene or protein, into the penises of hypercholesterolemic mice increases cavernous angiogenesis, eNOS phosphorylation, and cGMP expression, resulting in full recovery of erectile function and cavernous blood flow up to 8 weeks after treatment. COMP-Ang1-induced promotion of cavernous angiogenesis and erectile function was abolished in Nos3(-/-) mice and in the presence of the NOS inhibitor, L-NAME. COMP-Ang1 also restored the integrity of endothelial cell-cell junction by down-regulating the expression of histone deacetylase 2 in the penis of hypercholesterolemic mice and in primary cultured mouse cavernous endothelial cells. These findings constitute a new paradigm toward curative treatment of both cavernous angiopathy and ED.
authors.affiliation: 1] National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Republic of Korea [2] Inha Research Institute for Medical Sciences, Inha University School of Medicine, Incheon 400-711, Republic of Korea.
authors.forename: Ji-Kan
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Republic of Korea.
authors.forename: Woo Jean
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: National Research Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Koh
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Republic of Korea.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Piao
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Republic of Korea.
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: Jin
authors.affiliation: 1] Department of Internal Medicine and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea [2] Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Republic of Korea.
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Choi
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Republic of Korea.
authors.forename: Hwa-Yean
authors.initials: HY
authors.lastname: Shin
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Republic of Korea.
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Kwon
authors.affiliation: National Research Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Keehoon
authors.initials: K
authors.lastname: Jung
authors.affiliation: National Research Laboratory of Vascular Biology and Stem Cells and Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Republic of Korea.
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Suh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000098:blood supply / Q000378:metabolism*; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D012039:Regional Blood Flow; D062725:Tight Junction Proteins / Q000378:metabolism
chemical_list: C515576:COMP-Ang1 fusion protein; D011993:Recombinant Fusion Proteins; D062725:Tight Junction Proteins; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D056464:Histone Deacetylase 2; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester