Cerebral angiogenic factors, angiogenesis, and physiological response to chronic hypoxia differ among four commonly used mouse strains

Departments of 1 Dermatology, 2 Anatomy, 3 Neurosciences, and 4 Pathology, Case Western Reserve University, Cleveland, Ohio; and 5 Departments of Psychology, Human Anatomy, and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada Submitted 17 August 2006 ; accepted in final form 9 January 2007 Angiogenesis is a critical element for adaptation to low levels of oxygen and occurs following long-term exposure to mild hypoxia in rats. To test whether a similar response in mice occurs, CD1, 129/Sv, C57Bl/6, and Balb/c mice were exposed to 10% oxygen for up to 3 wk. All mice showed significant increases in the percentage of packed red blood cells, and CD1 and 129/Sv mice showed increased respiration frequency and minute volume, common physiological measures of hypoxia. Significant angiogenesis was observed in all strains except Balb/c following 3-wk exposure to chronic hypoxia. CD1 hypoxic mice had the largest increase (88%), followed by C57Bl/6 (48%), 129/Sv (41%), and Balb/c (12%), suggesting that some mice undergo more remodeling than others in response to hypoxia. Protein expression analysis of vascular endothelial growth factor (VEGF), angiopoietin (Ang)-1 and Ang2, and Tie2 were examined to determine whether regulation of different angiogenic proteins could account for the differences observed in hypoxia-induced angiogenesis. CD1 mice showed the strongest upregulation of VEGF, Ang2, Ang1, and Tie2, whereas Balb/c had only subtle increases in VEGF and no change in the other proteins. C57Bl/6 mice showed a regulatory response that fell between the CD1 and Balb/c mice, consistent with the intermediate increase in angiogenesis. Our results suggest that genetic heterogeneity plays a role in angiogenesis and regulation of angiogenic proteins and needs to be accounted for when designing and interpreting experiments using transgenic mice and when studying in vivo models of angiogenesis. vascular endothelial growth factor; angiopoietin; endothelial cell; genetic heterogeneity; plasticity Address for reprint requests and other correspondence: N. L. Ward, Dept. of Dermatology, Case Western Reserve Univ., School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106 (e-mail: nicole.ward{at}case.edu )