In this issue of the JCI
, Kondo and colleagues (6
) have utilized a clever genetic system in mice to probe the role of insulin and IGF signaling in this experimental model of relative hypoxia. They use two different genetically altered lines of mice, one of which contains an insulin receptor (IR) gene that can be deleted in the presence of Cre recombinase (7
), resulting in an absence of the IR in all cells that have expressed the recombinase, and a similar line that contains an IGF-1 receptor (IGF-1R) gene that can be deleted in the presence of the recombinase (8
). Experimental animals are bred to be homozygous for either of the modified receptor genes and to carry a transgene that expresses Cre recombinase under the control of the Tie-2 promoter/enhancer (9
). The endothelium in these animals is systemically devoid of the IR or IGF-IR, and referred to as vascular endothelial insulin receptor knockout (VENIRKO) and vascular endothelial insulin-like growth factor receptor knockout (VENIFARKO), respectively. While neither Kondo et al. (6
) nor Vicent et al. (10
) confirm the loss of IR or IGF-1R proteins, it is presumed that the loss is nearly complete given the severe reduction in message detected by quantitative PCR amplification of endothelial cell RNA from these mice and the careful description of the Tie2-Cre transgenic line (9
). The results are quite interesting.
First, Kondo (6
) and Vicent (10
) found no developmental or physiological consequences of IR or IGF-1R loss in endothelium; i.e., no gross or histological changes in the vasculature, and no metabolic changes such as those seen in subsets of the tissue-specific knockouts for each of these receptors (reviewed in ref. 11
). However, when young mice are put through the relative hypoxia protocol there are distinct differences between control mice and those with an absence of the IR or IGF-1R in the endothelium. They find reduced neovascularization, and concomitantly less immunoreactivity for markers of neovascularization including, VEGF, eNOS, and ET-1 in VENIRKO and to a lesser extent in VENIFARKO mice, compared to wild-type mice. One cannot exclude the possibility that the reduction of VEGF, eNOS, and ET-1 is simply because there are fewer endothelial cells to express these proteins. Nonetheless, this result is interesting because deficiencies in the IR and the IGF-1R signaling pathways are critically linked to metabolic defects in Type I and Type II diabetes and insulin resistance — disease states where neovascularization is a frequent complication.