title: Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease.
abstract: Moyamoya disease is a rare steno-occlusive cerebrovascular disorder often resulting in hemorrhagic and ischemic strokes. Although sharing the same ischemic stimulus with atherosclerotic cerebrovascular disease, Moyamoya disease is characterized by a highly instable cerebrovascular system which is prone to rupture due to pathological neovascularization. To understand the molecular mechanisms underlying this instability, angiopoietin-2 gene expression was analyzed in middle cerebral artery lesions obtained from Moyamoya disease and atherosclerotic cerebrovascular disease patients. Angiopoietin-2 was significantly up-regulated in Moyamoya vessels, while serum concentrations of soluble angiopoietins were not changed. For further evaluations, cerebral endothelial cells incubated with serum from these patients in vitro were applied. In contrast to atherosclerotic cerebrovascular disease serum, Moyamoya disease serum induced an angiopoietin-2 overexpression and secretion, accompanied by loss of endothelial integrity. These effects were absent or inverse in endothelial cells of non-brain origin suggesting brain endothelium specificity. The destabilizing effects on brain endothelial cells to Moyamoya disease serum were partially suppressed by the inhibition of angiopoietin-2. Our findings define brain endothelial cells as the potential source of vessel-destabilizing factors inducing the high plasticity state and disintegration in Moyamoya disease in an autocrine manner. We also provide new insights into Moyamoya disease pathophysiology that may be helpful for preventive treatment strategies in future.
authors.affiliation: 1 Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kinga G
authors.initials: KG
authors.lastname: Blecharz
authors.affiliation: 2 Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Frey
authors.affiliation: 1 Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schenkel
authors.affiliation: 2 Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Prinz
authors.affiliation: 3 Laboratory of Cellular Neurobiology, Neurology Unit, UCV, Milan, Italy.|4 Neurological Institute "C. Besta", Milan, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bedini
authors.affiliation: 5 Institute of Clinical Physiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Krug
authors.affiliation: 2 Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Czabanka
authors.affiliation: 1 Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Josephin
authors.initials: J
authors.lastname: Wagner
authors.affiliation: 5 Institute of Clinical Physiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
authors.affiliation: 6 Neurology Unit, UCV, Milan, Italy.|7 Neurological Institute "C. Besta", IRCCS Foundation, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bersano
authors.affiliation: 1 Department of Experimental Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.|2 Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Berlin, Germany.|8 Center of Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
mesh_terms: D000328:Adult; D042702:Angiopoietin-2 / Q000097:blood* / Q000235:genetics; D000818:Animals; D019898:Autocrine Communication / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D002560:Cerebrovascular Circulation / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D002537:Intracranial Arteriosclerosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020768:Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology*; D009072:Moyamoya Disease / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D042702:Angiopoietin-2
keywords: Moyamoya; angiogenesis; cell culture; cerebrovascular disease; stroke