title: Deficiency of endothelium-specific transcription factor Sox17 induces intracranial aneurysm.
abstract: BACKGROUND
  Intracranial aneurysm (IA) is a common vascular disorder that frequently leads to fatal vascular rupture. Although various acquired risk factors associated with IA have been identified, the hereditary basis of IA remains poorly understood. As a result, genetically modified animals accurately modeling IA and related pathogenesis have been lacking, and subsequent drug development has been delayed.
  
  
  RESULTS
  The transcription factor Sox17 is robustly expressed in endothelial cells of normal intracerebral arteries. The combination of Sox17 deficiency and angiotensin II infusion in mice induces vascular abnormalities closely resembling the cardinal features of IA such as luminal dilation, wall thinning, tortuosity, and subarachnoid hemorrhages. This combination impairs junctional assembly, cell-matrix adhesion, regeneration capacity, and paracrine secretion in endothelial cells of intracerebral arteries, highlighting key endothelial dysfunctions that lead to IA pathogenesis. Moreover, human IA samples showed reduced Sox17 expression and impaired endothelial integrity, further strengthening the applicability of this animal model to clinical settings.
  
  
  CONCLUSIONS
  Our findings demonstrate that Sox17 deficiency in mouse can induce IA under hypertensive conditions, suggesting Sox17 deficiency as a potential genetic factor for IA formation. The Sox17-deficient mouse model provides a novel platform to develop therapeutics for incurable IA.
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Seungjoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Il-Kug
authors.initials: IK
authors.lastname: Kim
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Dong-Cheol
authors.initials: DC
authors.lastname: Woo
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Sang-Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Sukhyun
authors.initials: S
authors.lastname: Song
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Hyung-Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.).
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: From Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea (S.L., I.-K.K., S.S., G.Y.K., I.K.); Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea (J.S.A.); Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (D.-C.W., S.-T.K.); Department of Forensic Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (H.-S.K.); and Department of Physiology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea (B.H.J.). injunek@kaist.ac.kr.
authors.forename: Injune
authors.initials: I
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001011:Aorta / Q000473:pathology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000737:chemistry / Q000473:pathology; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000096:biosynthesis / Q000235:genetics; D004108:Dilatation, Pathologic / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D024002:HMGB Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000150:complications; D002532:Intracranial Aneurysm / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000737:chemistry; D019899:Paracrine Communication; D034622:RNA Interference; D055760:SOXF Transcription Factors / Q000032:analysis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013345:Subarachnoid Hemorrhage / Q000209:etiology; D014158:Transcription, Genetic; D015854:Up-Regulation; D014680:Veins / Q000737:chemistry
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D024002:HMGB Proteins; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; D000804:Angiotensin II
keywords: cerebrovascular disorders; endothelial cells; intracranial aneurysm; transcription factors