Dysregulation of RNF213 promotes cerebral hypoperfusion

• Published in: Scientific reports Vol. 8; no. 1; pp. 3607 - 9
• Main Authors: Morimoto, Takaaki, Enmi, Jun-ichiro, Hattori, Yorito, Iguchi, Satoshi, Saito, Satoshi, Harada, Kouji H., Okuda, Hiroko, Mineharu, Yohei, Takagi, Yasushi, Youssefian, Shohab, Iida, Hidehiro, Miyamoto, Susumu, Ihara, Masafumi, Kobayashi, Hatasu, Koizumi, Akio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-02-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 59/57; 631/208/727/2000; 64/60; 692/617/375/534; Angiogenesis; Blood flow; Carotid artery; Cerebral blood flow; Cortex; Endothelial cells; Genotypes; Humanities and Social Sciences; Labeling; Magnetic resonance imaging; Moyamoya disease; multidisciplinary; Rodents; Science; Science (multidisciplinary); Stenosis; Surgery; Transgenic mice
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-22064-8

RNF213
is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of
RNF213
in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on
Rnf213
knockout (KO) and vascular endothelial cell-specific
Rnf213
mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin-labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%;
p
 = 0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%;
p
 = 0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of
RNF213
in the maintenance of CBF.