title: Impaired recovery of blood flow after hind-limb ischemia in mice lacking guanylyl cyclase-A, a receptor for atrial and brain natriuretic peptides.
abstract: OBJECTIVE
  Atrial and brain natriuretic peptides (ANP and BNP, respectively) function via guanylyl cyclase (GC)-A, resulting in diuresis, natriuresis, and blood vessel dilation. Here, we investigated the role of endogenous ANP/BNP-GC-A signaling on reparative vascular remodeling using a hind-limb ischemia model.
  
  
  RESULTS
  In GC-A-deficient mice (GC-A-KO), hind-limb ischemia resulted in autoamputation or severe ulcers in 60% of mice (6/10) during the 28-day observation period. In wild-type (WT) mice, partial amputation or mild ulcers were detected in only 20% of mice (2/10). Laser Doppler perfusion imaging revealed that the recovery of blood flow in the ischemic limb was significantly inhibited in GC-A-KO mice compared with WT mice. Immunostainings with anti-PECAM-1 antibody demonstrated that, in GC-A-KO, the capillary density of the ischemic tissue was significantly diminished compared to WT. Furthermore, bone marrow transplantation showed the predominant role of GC-A on local ischemic tissue rather than on vascular progenitor cells mobilized from bone marrow during vascular remodeling. In cultured human endothelial cells, ANP treatment significantly stimulated mRNA expressions of vascular endothelial growth factor and endothelial nitric oxide synthase via Erk1/2-dependent mechanism.
  
  
  CONCLUSIONS
  These results suggest that endogenous ANP and BNP play important roles in reparative vascular remodeling in ischemic tissue.
authors.affiliation: Research Institute, National Cardiovascular Center, Suita, Osaka 565-8565, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokudome
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yamahara
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Osaki
authors.forename: Naoto
authors.initials: N
authors.lastname: Minamino
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horio
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Sawai
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Mikiya
authors.initials: M
authors.lastname: Miyazato
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000502:physiology; D001808:Blood Vessels / Q000473:pathology / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010750:Phosphoproteins / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology*; D012038:Regeneration; D012039:Regional Blood Flow; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000098662:Vasodilator-Stimulated Phosphoprotein; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D052250:Nitric Oxide Synthase Type III; D048049:Extracellular Signal-Regulated MAP Kinases; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A