title: Overexpression of vascular endothelial growth factor in the germinal matrix induces neurovascular proteases and intraventricular hemorrhage.
abstract: Intracranial hemorrhage in preterm neonates may result in neonatal mortality and functional disabilities, but its pathogenic mechanisms are poorly defined and better therapies are needed. We used a tetracycline-regulated transgenic system to test whether the induction of vascular endothelial growth factor (VEGF) in the germinal matrix leads to intracranial hemorrhage. This genetic strategy initially induced a dense network of loosely adjoined endothelial cells and pericytes near lateral ventricles, similar to the immature vascular rete in human fetal brains. Yet, this rich vascular network transformed into low-vasculature patches correlated with hemorrhage and caspase-3 activation near birth. Gene expression and biochemical analyses suggested that downstream mediators of VEGF in this network include transcriptional factors ETS1 and HIF2α (hypoxia-inducible factor 2α), components of the PDGFβ (platelet-derived growth factor β) and TGFβ (transforming growth factor-β) receptor signaling pathways, matrix metalloproteinase-9 (MMP-9), and cathepsins. Prenatal administration of glucocorticoids markedly reduced mortality and cerebral hemorrhage in mutant animals, as in human neonates. This protective effect was not due to blocking vasculogenesis, but was instead associated with inhibition of neurovascular proteases, notably MMP-9, cathepsin B, and caspase-3. Collectively, these results support a causative role of VEGF in perinatal cerebral hemorrhage and implicate its downstream proteases as potential therapeutic targets.
authors.affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Dianer
authors.initials: D
authors.lastname: Yang
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Baumann
authors.forename: Yu-Yo
authors.initials: YY
authors.lastname: Sun
authors.forename: Mianzhi
authors.initials: M
authors.lastname: Tang
authors.forename: Richard Scott
authors.initials: RS
authors.lastname: Dunn
authors.forename: Ann L
authors.initials: AL
authors.lastname: Akeson
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kernie
authors.forename: Suhas
authors.initials: S
authors.lastname: Kallapur
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lindquist
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Stanley Steven
authors.initials: SS
authors.lastname: Potter
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Liang
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001623:Betamethasone / Q000494:pharmacology / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010447:Peptide Hydrolases / Q000096:biosynthesis*; D010641:Phenotype; D016548:Prosencephalon / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013752:Tetracycline / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011480:Protease Inhibitors; D042461:Vascular Endothelial Growth Factor A; D001623:Betamethasone; D010447:Peptide Hydrolases; D053148:Caspase 3; D002401:Cathepsin B; D020780:Matrix Metalloproteinase 9; D013752:Tetracycline