The long-term objectives of this proposal are to explore the roles of angiogenesis in the brain, especially the role of brain arteriovenous malformations (BAVMs). We have intensively studied BAVM tissue removed during surgery. We will continue this study and develop an in vivo animal model of non-tumor angiogenesis relevant to cerebrovascular diseases including BAVMs. In vivo gene transfer into the brain with adenoviral vectors provides a useful tool inducing focal, non-tumor angiogenesis in the adult rodent brain. The PI has used this technique to induce stable overexpression of a variety of genes in the mouse brain. We hypothesize that adenoviral-mediated vascular endothelial growth factor (VEGF) gene transduction into the mouse brain induces VEGF overexpression. VEGF signaling, combined with VEGF-induced upregulation of the angiopoietin/Tie-2 signaling pathway, stimulates focal vascular network formation. Furthermore, transforming growth factor beta-1 (TGF-b1) activates TGF-b1, ALK-5, and Smad 2/3 signal pathways, promoting regional angiogenesis formation in the brain tissue.
The specific aims of this proposal are to determine: 1) whether VEGF protein production will be increased following adenoviral-VEGF (AdVEGF) gene transfer in the adult mouse brain, and whether overexpression of VEGF will induce focal clusters of microvasculature formation; 2) whether TbR-ll, ALK5, and Smad 2/3 will be upregulated in the TGF-bl transgenic mouse brain following AdVEGF gene transduction. Furthermore, to quantify whether endothelial cell proliferation and support cell differentiation will be increased, and finally, to identify how mature these neo-microvasculature are in the mouse brain with both TGF-b1 and VEGF overexpression. The experimental components include: 1) highly reproducible adenoviral vector gene transfer in mice; 2) specific VEGF and TGF-b1 pathway detection; and 3) using unique TGF-b transgenic mice. Combining these genetic techniques may lead to the development of a novel, reproducible, and useful animal model. This non-tumor angiogenesis rodent preparation will serve as a model of disordered human cerebral angiogenesis, leading relatively quickly to the ability to test new therapeutic approaches for cerebrovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS045123-02
Application #
6752081
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Jacobs, Tom P
Project Start
2003-06-01
Project End
2005-11-30
Budget Start
2004-06-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2004
Total Cost
$179,906
Indirect Cost
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Yao, Jianhua S; Zhai, Wenwu; Fan, Yongfeng et al. (2007) Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells. J Cereb Blood Flow Metab 27:510-20
Shen, Fanxia; Su, Hua; Liu, Weizhong et al. (2006) Recombinant adeno-associated viral vector encoding human VEGF165 induces neomicrovessel formation in the adult mouse brain. Front Biosci 11:3190-8
Zhu, Yiqian; Lawton, Michael T; Du, Rose et al. (2006) Expression of hypoxia-inducible factor-1 and vascular endothelial growth factor in response to venous hypertension. Neurosurgery 59:687-96; discussion 687-96
Yao, Jianhua S; Zhai, Wenwu; Young, William L et al. (2006) Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: the role for KDR and MMP-9. Biochem Biophys Res Commun 342:1396-404
Zhu, Y; Shwe, Y; Du, R et al. (2006) Effects of angiopoietin-1 on vascular endothelial growth factor-induced angiogenesis in the mouse brain. Acta Neurochir Suppl 96:438-43
Zhu, Yiqian; Lee, Chanhung; Shen, Fanxia et al. (2005) Angiopoietin-2 facilitates vascular endothelial growth factor-induced angiogenesis in the mature mouse brain. Stroke 36:1533-7
Xu, Bin; Wu, Yong Qin; Huey, Madeleine et al. (2004) Vascular endothelial growth factor induces abnormal microvasculature in the endoglin heterozygous mouse brain. J Cereb Blood Flow Metab 24:237-44
Yao, Jianhua S; Chen, Yongmei; Zhai, Wenwu et al. (2004) Minocycline exerts multiple inhibitory effects on vascular endothelial growth factor-induced smooth muscle cell migration: the role of ERK1/2, PI3K, and matrix metalloproteinases. Circ Res 95:364-71