title: Endoglin deficiency in bone marrow is sufficient to cause cerebrovascular dysplasia in the adult mouse after vascular endothelial growth factor stimulation.
abstract: OBJECTIVE
  Bone marrow-derived cells (BMDCs) home to vascular endothelial growth factor (VEGF)-induced brain angiogenic foci, and VEGF induces cerebrovascular dysplasia in adult endoglin heterozygous (Eng(+/-)) mice. We hypothesized that Eng(+/-) BMDCs cause cerebrovascular dysplasia in the adult mouse after VEGF stimulation.
  
  
  METHODS
  BM transplantation was performed using adult wild-type (WT) and Eng(+/-) mice as donors/recipients. An adeno-associated viral vector expressing VEGF was injected into the basal ganglia 4 weeks after transplantation. Vascular density, dysplasia index (vessels >15 µm/100 vessels), and BMDCs in the angiogenic foci were analyzed.
  
  
  RESULTS
  The dysplasia index of WT/Eng(+/-) BM mice was higher than WT/WT BM mice (P<0.001) and was similar to Eng(+/-)/Eng(+/-) BM mice (P=0.2). Dysplasia in Eng(+/-) mice was partially rescued by WT BM (P<0.001). WT/WT BM and WT/Eng(+/-) BM mice had similar numbers of BMDCs in the angiogenic foci (P=0.4), most of which were CD68(+). Eng(+/-) monocytes/macrophages expressed less matrix metalloproteinase-9 and Notch1.
  
  
  CONCLUSIONS
  Endoglin-deficient BMDCs are sufficient for VEGF to induce vascular dysplasia in the adult mouse brain. Our data support a previously unrecognized role of BM in the development of cerebrovascular malformations.
authors.affiliation: UCSF, Department of Anesthesia and Perioperative Care, San Francisco, CA 94110, USA.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Choi
authors.forename: Espen J
authors.initials: EJ
authors.lastname: Walker
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.forename: Kristine
authors.initials: K
authors.lastname: Jun
authors.forename: Robert
authors.initials: R
authors.lastname: Kuo
authors.forename: John
authors.initials: J
authors.lastname: Pile-Spellman
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: William L
authors.initials: WL
authors.lastname: Young
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002561:Cerebrovascular Disorders / Q000139:chemically induced*; D000071063:Endoglin; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009000:Monocytes / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects* / Q000494:pharmacology; D054079:Vascular Malformations / Q000139:chemically induced*
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A; D020780:Matrix Metalloproteinase 9