Genetic loci that control vascular endothelial growth factor-induced angiogenesis

Angiogenesis is regulated by the balance between angiogenic stimulators and inhibitors. Numerous reports have demonstrated that tumors induce aggressive angiogenesis by up-regulating the production of angiogenesis stimulating growth factors to overcome the baseline levels of endogenous inhibitors. However, the possibility of large differences in the host's responsiveness to angiogenic factors has been largely overlooked. Using the corneal micropocket neovascularization assay, we have observed >10-fold differences in responsiveness to either basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) among various mouse strains. The inheritance pattern observed for these traits supported a QTL (quantitative trait locus) approach to mapping the genes responsible for the differences in angiogenic responsiveness. To overcome variability in the assay, we used recombinant inbred lines to map this phenotype. In the BXD series of recombinant inbred mouse strains, we have mapped the regions responsible for regulating VEGF-induced angiogenesis using both composite interval mapping and multiple interval mapping. Both approaches link VEGF responsiveness to regions on chromosomes 2 (near D2Mit6) and 10 (near D10Mit20). Candidate angiogenesis-related genes in these regions include those for collagen XVIII/endostatin, matrix metalloproteinase 11, integrin beta2, prostaglandin D2 synthase, and interleukin-1 receptor antagonist.