A novel Flk1-TVA transgenic mouse model for gene delivery to angiogenic vasculature.
The genes that regulate the formation of blood vessels in adult tissues represent promising therapeutic targets because angiogenesis plays a role in many diseases, including cancer. We wished to develop a mouse model allowing characterization of gene function in adult angiogenic vasculature while minimizing effects on embryonic vasculature or adult quiescent vasculature. Here we describe a transgenic mouse model that allows expression of proteins in the endothelial cells of newly forming blood vessels in the adult using a selective retroviral gene delivery system. We generated transgenic mouse lines that express the TVA receptor for the RCAS avian-specific retrovirus from Flk1 gene regulatory elements that drive expression in proliferating endothelial cells. Several of these Flk1-TVA lines expressed TVA mRNA in the embryonic vasculature and TVA protein in new blood vessels growing into subcutaneous extracellular matrix implants in adult mice. In a Flk1-TVA line that was crossed with the MMTV-PyMT transgenic mammary tumor model, tumor endothelial cells also expressed the TVA protein. Furthermore, endothelial cells in extracellular matrix implants and the tumors of Flk1-TVA mice were susceptible to RCAS infection, as determined by expression of green fluorescent protein encoded by the virus. The Flk1-TVA mouse model in conjunction with the RCAS gene delivery system will be useful to study molecular mechanisms underlying adult forms of angiogenesis.
Vervoort
Virginie S
VS
Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Lu
Mark
M
Valencia
Fatima
F
Lesperance
Jacqueline
J
Breier
Georg
G
Oshima
Robert
R
Pasquale
Elena B
EB
D001355:Alpharetrovirus / Q000235:genetics; D000818:Animals; D030161:Avian Proteins / Q000235:genetics*; D001808:Blood Vessels / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004198:Disease Susceptibility; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000235:genetics; D011991:Receptors, Virus / Q000235:genetics*; D012192:Retroviridae Infections / Q000235:genetics; D020079:Terminal Repeat Sequences / Q000235:genetics; D019076:Transgenes; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
D030161:Avian Proteins; D011991:Receptors, Virus; C088745:Tva receptor; D040301:Vascular Endothelial Growth Factor Receptor-2