Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation.
Loss-of-function activin receptor-like kinase 1 gene mutation (ALK1+/-) is associated with brain arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia type 2. Other determinants of the lesional phenotype are unknown. In the present study, we investigated the influence of high vascular flow rates on ALK1+/- mice by manipulating cerebral blood flow (CBF) using vasodilators. Adult male ALK1+/- mice underwent adeno-associated viral-mediated vascular endothelial growth factor (AAVVEGF) or lacZ (AAVlacZ as a control) gene transfer into the brain. Two weeks after vector injection, hydralazine or nicardipine was infused intraventricularly for another 14 days. CBF was measured to evaluate relative tissue perfusion. We analyzed the number and morphology of capillaries. Results demonstrated that hydralazine or nicardipine infusion increased focal brain perfusion in all mice. It was noted that focal CBF increased most in AAVVEGF-injected ALK1+/- mice following hydralazine or nicardipine infusion (145+/-23% or 150+/-11%; P<0.05). There were more detectable dilated and dysplastic capillaries (2.4+/-0.3 or 2.0+/-0.4 dysplasia index; P<0.01) in the brains of ALK1+/- mice treated with AAVVEGF and hydralazine or nicardipine compared with the mice treated with them individually. We concluded that increased focal tissue perfusion and angiogenic factor VEGF stimulation could have a synergistic effect to promote capillary dysplasia in a genetic deficit animal model, which may have relevance to further studies of AVMs.
Hao
Qi
Q
University of California, San Francisco, Department of Anesthesia and Perioperative Care, 1001 Potrero Ave., Rm. 3C-38, San Francisco, CA 94110, USA.
Su
Hua
H
Marchuk
Douglas A
DA
Rola
Radoslaw
R
Wang
Yongqiang
Y
Liu
Weizhong
W
Young
William L
WL
Yang
Guo-Yuan
GY
D030201:Activin Receptors, Type I / Q000172:deficiency* / Q000235:genetics; D030301:Activin Receptors, Type II; D000818:Animals; D001921:Brain / Q000098:blood supply*; D002196:Capillaries / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005822:Genetic Vectors; D006830:Hydralazine / Q000008:administration & dosage; D021621:Imaging, Three-Dimensional; D007263:Infusions, Parenteral; D002538:Intracranial Arteriovenous Malformations / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic; D009529:Nicardipine / Q000008:administration & dosage; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014665:Vasodilator Agents / Q000008:administration & dosage
D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; D006830:Hydralazine; D009529:Nicardipine; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse