title: Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease.
abstract: Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disease with unknown etiology that is characterized by the development of abnormal vascular networks at the base of the brain. Recent genome-wide studies identified RNF213 as an important MMD susceptibility gene. However, the exact mechanism by which the RNF213 abnormality leads to MMD remains unknown. Thus, we sought to clarify the role of RNF213 in angiogenesis under ischemic conditions using conventional RNF213 knockout mice. We assessed the infarction volume, cerebral edema, and vascular density in the ischemic brain after transient middle cerebral artery occlusion (tMCAO). To further evaluate systemic angiogenesis following chronic ischemia, we investigated blood flow recovery using laser speckle flowmetry, the severity of ambulatory impairments, and vascular density in the hind-limb after permanent femoral artery ligation. Results were compared between homozygous RNF213 knockout mice (RNF213 -/-) and wild-type littermates (Wt). No significant differences were observed in infarction volume or the formation of edema following tMCAO, or in vascular density 28 days after tMCAO between RNF213 -/- and Wt. Blood flow recovery was significantly improved in RNF213 -/- from 3 to 28 days after femoral artery ligation, and angiogenesis as shown by vascular density in the hind-limb was significantly enhanced in RNF213 -/- at 28 days. The amelioration of ambulatory impairments was also evident in RNF213 -/-. Angiogenesis was enhanced in mice lacking RNF213 after chronic hind-limb ischemia, which suggested the potential role of the RNF213 abnormality in the development of pathological vascular networks in chronic ischemia.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: fujimur@nsg.med.tohoku.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Fujimura
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Niizuma
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kanoke
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakata
authors.affiliation: Department of Molecular Biology, Tohoku University Institute of Aging and Cancer, Sendai, Japan.
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Morita-Fujimura
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000251:Adenosine Triphosphatases; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics*; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply; D007150:Immunohistochemistry; D007511:Ischemia / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009072:Moyamoya Disease / Q000235:genetics* / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics
chemical_list: C583291:RNF213 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
keywords: Angiogenesis; Ischemia; Moyamoya disease; RNF213; Target disruption