Del-1 gene transfer induces cerebral angiogenesis in mice.
Developmental endothelial locus-1 (Del-1) is a novel angiomatrix protein that has been shown to stimulate a potent angiogenic response and promote functional recovery in hind-limb and cardiac ischemia in animal models; however, its impact on cerebral angiogenesis is unknown. In this study, we investigated whether Del-1 overexpression via gene transfer induces cerebral angiogenesis in a murine model, and examined Del-1 expression after ischemic stroke. Cerebral Del-1 overexpression was achieved with AAV (adeno-associated virus) transduction system via stereotactic injection. Control mice were injected with AAV-lacZ. Del-1 gene transduction led to a significant induction of cerebral angiogenesis compared to AAV-lacZ treatment at 4 weeks after gene transfer (Del-1: 97+/-7 vs lacZ: 64+/-28, vessels/field, p<0.05). Mice transduced with AAV-Del-1 showed significantly elevated vascular densities for up to 6 weeks after gene delivery. In addition, double immunofluorescent staining showed co-localization of endothelial cell marker CD31 with BrdU (specific marker for proliferating cells), indicating that Del-1 promoted endogenous endothelial cell proliferation and angiogenesis. Our immunohistochemical staining also showed that Del-1 expression was markedly up-regulated in the peri-infarct area at 3 days after permanent focal cerebral ischemia compared to the sham-operated non-ischemic control. Our data suggest that Del-1 may participate in modulating cerebral angiogenesis, and that gene transfer of Del-1 may provide a novel and potent means for stimulating cerebral angiogenesis.
Fan
Yongfeng
Y
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110, USA.
Zhu
Wei
W
Yang
Michael
M
Zhu
Yiqian
Y
Shen
Fanxia
F
Hao
Qi
Q
Young
William L
WL
Yang
Guo-Yuan
GY
Chen
Yongmei
Y
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000628:therapy*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D015815:Cell Adhesion Molecules; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000098:blood supply; D000229:Dependovirus / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*; D014162:Transfection / Q000379:methods
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C491706:Edil3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D001973:Bromodeoxyuridine