Retroviral delivery of homeobox D3 gene induces cerebral angiogenesis in mice.
Angiogenesis is regulated by concerted actions of angiogenic and angiostatic factors. Homeobox D3 gene (HOXD3) is a potent proangiogenic transcription factor that promotes angiogenesis by modulating the expression of matrix-degrading proteinases, integrins, and extracellular matrix components. Application of HOXD3 can promote angiogenesis in the skin, but its role in other vascular beds has not been examined. The authors examined HOXD3 expression in human brain vessels by in situ hybridization. Although little or no HOXD3 mRNA was detected in normal brain vessels, increased levels of HOXD3 and its target gene, alpha V beta 3, were found in angiogenic vessels in human brain arteriovenous malformations. The authors further investigated whether HOXD3 plays a role in cerebral angiogenesis in a murine model. Expression of HOXD3 in mouse brain was achieved through retroviral vector-mediated HOXD3 gene transfer. HOXD3 expression lead to a significant induction of cerebral angiogenesis as shown by quantitative microvessel counting (HOXD3: 241 +/- 19 vessels/mm2 vs. saline: 150 +/- 14 vessels/mm2, P < 0.05). The data also showed that focal cerebral blood flow was increased in the angiogenic region with less vascular leakage. Moreover, expression of HOXD3 led to an increase in the expression of a direct downstream target gene alpha V beta 3 integrin. The data suggest that HOXD3 may play an important role in regulating cerebral angiogenesis, and that gene transfer of HOXD3 may provide a novel and potent means to stimulate angiogenesis.
Chen
Yongmei
Y
Department of Anesthesia and Perioperative Care, The Center for Cerebrovascular Research, University of California, San Francisco, California 94410, USA.
Xu
Bin
B
Arderiu
Gemma
G
Hashimoto
Tomoki
T
Young
William L
WL
Boudreau
Nancy
N
Yang
Guo-Yuan
GY
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000098:blood supply* / Q000378:metabolism*; D049109:Cell Proliferation; D002560:Cerebrovascular Circulation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D018398:Homeodomain Proteins; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics*; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D039302:Integrin alphaVbeta3; D012333:RNA, Messenger; D014157:Transcription Factors; C073547:HOXA4 protein, human