title: Expression of the apelin-APJ pathway and effects on erectile function in a mouse model of vasculogenic erectile dysfunction.
abstract: BACKGROUND
  Much attention has recently been focused on therapeutic angiogenesis as a treatment for erectile dysfunction (ED). The apelin and apelin receptor (APJ) system is known to cause endothelium-dependent vasodilatation and to be involved in angiogenesis.
  
  
  OBJECTIVE
  To examine the differential expression of apelin and APJ in animal models of vasculogenic ED and to determine whether and how enhancement of apelin-APJ signaling restores erectile function in hypercholesterolemic mice.
  
  
  METHODS
  Acute cavernous ischemia was induced in C57BL/6J mice by bilateral occlusion of internal iliac arteries, and chronic vasculogenic ED was induced by feeding a high-cholesterol diet or by intraperitoneal injection of streptozotocin.
  
  
  METHODS
  Messenger RNA (mRNA) levels of apelin and APJ were determined in cavernous tissue of each vasculogenic ED model by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). We evaluated erectile function by electrical stimulation of the cavernous nerve in hypercholesterolemic mice 1, 3, 7, and 14 days after a single intracavernous injection of apelin protein (5 μg/20 μL). The penis was harvested for histologic examinations and Western blot analysis.
  
  
  RESULTS
  The cavernous mRNA expression of apelin and APJ was up-regulated in acute ischemia model and down-regulated in chronic vasculogenic ED models. A significant restoration of erectile function was noted 1 day after injection of apelin protein into the penis of hypercholesterolemic mice; however, erectile function returned to baseline values thereafter. The beneficial effects of apelin on erectile function resulted mainly from an activation of endothelial nitric oxide synthase and increase in nitric oxide bioavailability through reduction in reactive oxygen species-mediated endothelial apoptosis rather than through direct endothelial cell proliferation.
  
  
  CONCLUSIONS
  These findings suggest that apelin-APJ signaling is a potential therapeutic target in the treatment of vasculogenic ED. Further studies are needed to develop a potent agonist for APJ and to determine the role of repeated dosing of apelin on long-term recovery of erectile function.
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Kwon
authors.forename: Buyankhuu
authors.initials: B
authors.lastname: Tuvshintur
authors.forename: Woo Jean
authors.initials: WJ
authors.lastname: Kim
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: Jin
authors.forename: Guo Nan
authors.initials: GN
authors.lastname: Yin
authors.forename: Kang-Moon
authors.initials: KM
authors.lastname: Song
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Choi
authors.forename: Ki-Dong
authors.initials: KD
authors.lastname: Kwon
authors.forename: Dulguun
authors.initials: D
authors.lastname: Batbold
authors.forename: Ji-Kan
authors.initials: JK
authors.lastname: Ryu
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Suh
mesh_terms: D054392:Adipokines; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D018783:Impotence, Vasculogenic / Q000188:drug therapy / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010410:Penile Erection; D010413:Penis / Q000098:blood supply*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D052250:Nitric Oxide Synthase Type III
keywords: Angiogenesis; Apelin; Endothelial Dysfunction; Erectile Dysfunction; Therapeutic Protein