Article

Retroviral delivery of homeobox D3 gene induces cerebral angiogenesis in mice.

Department of Anesthesia and Perioperative Care, The Center for Cerebrovascular Research, University of California, San Francisco, California 94410, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.34). 11/2004; 24(11):1280-7. DOI: 10.1097/01.WCB.0000141770.09022.AB
Source: PubMed

ABSTRACT 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.

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    • "What determines this specificity is currently unknown, but it seems likely that the a5 and b3 genes contain hypoxia-response elements. It has also been shown that retroviral delivery of the transcription factor HoxD3 to the brain promotes angiogenic sprouting, and strong induction of avb3 integrin on angiogenic capillaries (Chen et al, 2004). "
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    • "HoxD3 activates αvβ3 and uPA, resulting in the transformation of resting endothelial cells to an angiogenic state (Penta et al., 1999; Rezaee et al., 2002). We have previously reported that HoxD3 overexpression can induce brain angiogenesis (Chen et al., 2004). "
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