title: Endoglin deficiency impairs stroke recovery.
abstract: OBJECTIVE
  Endoglin deficiency causes hereditary hemorrhagic telangiectasia-1 and impairs myocardial repair. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia-1 are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that endoglin deficiency impairs stroke recovery.
  
  
  METHODS
  Eng heterozygous (Eng+/-) and wild-type mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Pial collateral vessels were quantified before pMCAO. Infarct/atrophic volume, vascular density, and macrophages were quantified in various days after pMCAO, and behavioral function was assessed using corner and adhesive removal tests on days 3, 15, 30, and 60 after pMCAO. The association between ENG 207G>A polymorphism and brain arteriovenous malformation rupture and surgery outcome was analyzed using logistic regression analysis in 256 ruptured and 157 unruptured patients.
  
  
  RESULTS
  After pMCAO, Eng+/- mice showed larger infarct/atrophic volumes at all time points (P<0.05) and showed worse behavior performance (P<0.05) at 15, 30, and 60 days when compared with wild-type mice. Eng+/- mice had fewer macrophages on day 3 (P=0.009) and more macrophages on day 60 (P=0.02) in the peri-infarct region. Although Eng+/- and wild-type mice had similar numbers of pial collateral vessels before pMCAO, Eng+/- mice had lower vascular density in the peri-infarct region (P=0.05) on day 60 after pMCAO. In humans, ENG 207A allele has been associated with worse outcomes after arteriovenous malformation rupture or surgery of patients with unruptured arteriovenous malformation.
  
  
  CONCLUSIONS
  Endoglin deficiency impairs brain injury recovery. Reduced angiogenesis, impaired macrophage homing, and delayed inflammation resolution could be the underlying mechanism.
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Fanxia
authors.initials: F
authors.lastname: Shen
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Pei-Lun
authors.initials: PL
authors.lastname: Chu
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Zhenying
authors.initials: Z
authors.lastname: Han
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Erick M
authors.initials: EM
authors.lastname: Westbroek
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Choi
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Douglas
authors.initials: D
authors.lastname: Marchuk
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lawton
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.affiliation: From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.). hua.su@ucsf.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Su
mesh_terms: D000483:Alleles; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D000071063:Endoglin; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D011110:Polymorphism, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface
keywords: angiogenesis effect; macrophages; telangiectasia, hereditary hemorrhagic