A high level of vascular endothelial growth factor (VEGF) has been implicated in brain arteriovenous malformation (bAVM) bleeding and rupture. However, direct evidence is missing. In this study the authors used a mouse bAVM model to test the hypothesis that elevation of focal VEGF levels in bAVMs exacerbates the severity of bAVM hemorrhage.
Brain AVMs were induced in adult mice in which activin receptor–like kinase 1 (Alk1, a gene that causes AVM) gene exons 4–6 were floxed by intrabasal ganglia injection of an adenoviral vector expressing Cre recombinase to induce Alk1 mutation and an adeno-associated viral vector expressing human VEGF (AAV-VEGF) to induce angiogenesis. Two doses of AAV-VEGF (5 × 109 [high] or 2 × 109 [low]) viral genomes were used. In addition, the common carotid artery and external jugular vein were anastomosed in a group of mice treated with low-dose AAV-VEGF 6 weeks after the model induction to induce cerebral venous hypertension (VH), because VH increases the VEGF level in the brain. Brain samples were collected 8 weeks after the model induction. Hemorrhages in the bAVM lesions were quantified on brain sections stained with Prussian blue, which detects iron deposition. VEGF levels were quantified in bAVM tissue by enzyme-linked immunosorbent assay.
Compared to mice injected with a low dose of AAV-VEGF, the mice injected with a high dose had higher levels of VEGF (p = 0.003) and larger Prussian blue–positive areas in the bAVM lesion at 8 or 9 weeks after model induction (p = 0.002). VH increased bAVM hemorrhage in the low-dose AAV-VEGF group. The overall mortality in the high-dose AAV-VEGF group was 26.7%, whereas no mouse died in the low-dose AAV-VEGF group without VH. In contrast, VH caused a mortality of 50% in the low-dose AAV-VEGF group.
Using mouse bAVM models, the authors provided direct evidence that elevation of the VEGF level increases bAVM hemorrhage and mouse mortality.
ABBREVIATIONSAAV = adeno-associated viral vector; Ad-Cre = adenoviral vector expressing Cre recombinase; Ad-GFP = adenoviral vector expressing green fluorescent protein; bAVM = brain arteriovenous malformation; CCA = common carotid artery; EJV = external jugular vein; IACUC = Institutional Animal Care and Use Committee; UCSF = University of California, San Francisco; VEGF = vascular endothelial growth factor; VH = venous hypertension; WT = wild type.
Al-Shahi SalmanR, WhitePM, CounsellCE, du PlessisJ, van BeijnumJ, JosephsonCB, : Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. 311:1661–1669, 201410.1001/jama.2014.3200)| false
BurkhardtJKChenXWinklerEACookeDLKimHLawtonMT: Delayed venous drainage in ruptured arteriovenous malformations based on quantitative color-coded digital subtraction angiography. World Neurosurg104:619–6272017
ChenW, SunZ, HanZ, JunK, CamusM, WankhedeM, : De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation. 45:900–902, 20142445729310.1161/STROKEAHA.113.003655)| false
ChoiEJWalkerEJDegosVJunKKuoRPile-SpellmanJ: Endoglin deficiency in bone marrow is sufficient to cause cerebrovascular dysplasia in the adult mouse after vascular endothelial growth factor stimulation. Stroke44:795–7982013
ChoiEJ, WalkerEJ, DegosV, JunK, KuoR, Pile-SpellmanJ, : Endoglin deficiency in bone marrow is sufficient to cause cerebrovascular dysplasia in the adult mouse after vascular endothelial growth factor stimulation. 44:795–798, 201310.1161/STROKEAHA.112.67197423306322)| false
ChoiEJWalkerEJShenFOhSPArthurHMYoungWL: Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse. Cerebrovasc Dis33:540–5472012
ChoiEJ, WalkerEJ, ShenF, OhSP, ArthurHM, YoungWL, : Minimal homozygous endothelial deletion of Eng with VEGF stimulation is sufficient to cause cerebrovascular dysplasia in the adult mouse. 33:540–547, 20122257195810.1159/000337762)| false
CockroftKMJayaramanMVAmin-HanjaniSDerdeynCPMcDougallCGWilsonJA: A perfect storm: how a randomized trial of unruptured brain arteriovenous malformations’ (ARUBA’s) trial design challenges notions of external validity. Stroke43:1979–19812012
DerdeynCPZipfelGJAlbuquerqueFCCookeDLFeldmannESheehanJP: Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke48:e200–e2242017
DerdeynCP, ZipfelGJ, AlbuquerqueFC, CookeDL, FeldmannE, SheehanJP, : Management of brain arteriovenous malformations: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. 48:e200–e224, 201710.1161/STR.0000000000000134)| false
HashimotoTEmalaCWJoshiSMesa-TejadaRQuickCMFengL: Abnormal pattern of Tie-2 and vascular endothelial growth factor receptor expression in human cerebral arteriovenous malformations. Neurosurgery47:910–9192000
KashiwazakiDKobayashiRHoukinKKurodaS: Increased expression of vascular endothelial growth factor and its receptor in enlarging brain arteriovenous malformations—a case report. Br J Neurosurg28:119–1212014
KashiwazakiD, KobayashiR, HoukinK, KurodaS: Increased expression of vascular endothelial growth factor and its receptor in enlarging brain arteriovenous malformations—a case report. 28:119–121, 201410.3109/02688697.2013.815325)| false
KoizumiTShiraishiTHagiharaNTabuchiKHayashiTKawanoT: Expression of vascular endothelial growth factors and their receptors in and around intracranial arteriovenous malformations. Neurosurgery50:117–1262002
KoizumiT, ShiraishiT, HagiharaN, TabuchiK, HayashiT, KawanoT: Expression of vascular endothelial growth factors and their receptors in and around intracranial arteriovenous malformations. 50:117–126, 200211844242)| false
MaLChenXLChenYWuCXMaJZhaoYL: Subsequent haemorrhage in children with untreated brain arteriovenous malformation: Higher risk with unbalanced inflow and outflow angioarchitecture. Eur Radiol27:2868–28762017
MohrJP, MoskowitzAJ, ParidesM, StapfC, YoungWL: Hull down on the horizon: A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) trial. 43:1744–1745, 201210.1161/STROKEAHA.112.653584)| false
MohrJPParidesMKStapfCMoqueteEMoyCSOverbeyJR: Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet383:614–6212014
MohrJP, ParidesMK, StapfC, MoqueteE, MoyCS, OverbeyJR, : Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. 383:614–621, 20142426810510.1016/S0140-6736(13)62302-8)| false
ParkSO, LeeYJ, SekiT, HongKH, FliessN, JiangZ, : ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. 111:633–642, 20081791138410.1182/blood-2007-08-107359)| false
ShenFWalkerEJJiangLDegosVLiJSunB: Coexpression of angiopoietin-1 with VEGF increases the structural integrity of the blood-brain barrier and reduces atrophy volume. J Cereb Blood Flow Metab31:2343–23512011
ShenF, WalkerEJ, JiangL, DegosV, LiJ, SunB, : Coexpression of angiopoietin-1 with VEGF increases the structural integrity of the blood-brain barrier and reduces atrophy volume. 31:2343–2351, 20112177231010.1038/jcbfm.2011.97)| false
SonsteinWJKaderAMichelsenWJLlenaJFHiranoACasperD: Expression of vascular endothelial growth factor in pediatric and adult cerebral arteriovenous malformations: an immunocytochemical study. J Neurosurg85:838–8451996
van BeijnumJ, van der WorpHB, BuisDR, Al-Shahi SalmanR, KappelleLJ, RinkelGJ, : Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. 306:2011–2019, 201110.1001/jama.2011.1632)| false