De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation.
OBJECTIVE
In humans, activin receptor-like kinase 1 (Alk1) deficiency causes arteriovenous malformations (AVMs) in multiple organs, including the brain. Focal Alk1 pan-cellular deletion plus vascular endothelial growth factor stimulation induces brain AVMs in the adult mouse. We hypothesized that deletion of Alk1 in endothelial cell (EC) alone plus focal vascular endothelial growth factor stimulation is sufficient to induce brain AVM in the adult mouse.


METHODS
Focal angiogenesis was induced in the brain of 8-week-old Pdgfb-iCreER;Alk1(2f/2f) mice by injection of adeno-associated viral vectors expressing vascular endothelial growth factor. Two weeks later, EC-Alk1 deletion was induced by tamoxifen treatment. Vascular morphology was analyzed, and EC proliferation and dysplasia index (number of vessels with diameter>15 μm per 200 vessels) were quantified 10 days after tamoxifen administration.


RESULTS
Tangles of enlarged vessels resembling AVMs were present in the brain angiogenic region of tamoxifen-treated Pdgfb-iCreER;Alk1(2f/2f) mice. Induced brain AVMs were marked by increased dysplasia index (P<0.001) and EC proliferation clustered within the dysplastic vessels. AVMs were also detected around the ear tag-wound and in other organs.


CONCLUSIONS
Deletion of Alk1 in EC in adult mice leads to an increased local EC proliferation during brain angiogenesis and de novo brain AVM.
From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (W.C., Z.H., K.J., M.C., M.W., L.M., W.L.Y., H.S.), Departments of Radiology (Z.S.), Pediatrics (T.A.), Neurological Surgery (W.L.Y.), and Neurology (W.L.Y.), University of California, San Francisco.
Wanqiu
W
Chen
Zhengda
Z
Sun
Zhenying
Z
Han
Kristine
K
Jun
Marine
M
Camus
Mamta
M
Wankhede
Lei
L
Mao
Tom
T
Arnold
William L
WL
Young
Hua
H
Su
D030201:Activin Receptors, Type I / Q000235:genetics* / Q000502:physiology*; D030301:Activin Receptors, Type II; D000256:Adenoviridae; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D049109:Cell Proliferation; D020785:Central Nervous System Vascular Malformations / Q000235:genetics* / Q000503:physiopathology*; D042783:Endothelial Cells / Q000502:physiology; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D051379:Mice; D030781:Organisms, Genetically Modified; D013629:Tamoxifen / Q000494:pharmacology; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D000963:Antimetabolites; D018931:Antineoplastic Agents, Hormonal; D042461:Vascular Endothelial Growth Factor A; D013629:Tamoxifen; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse; D001973:Bromodeoxyuridine
AVM (arteriovenous malformation) intracranial; models, animal; telangiectasia, hereditary hemorrhagic, type 2