Inhibition of aldose reductase prevents angiogenesis in vitro and in vivo

We have recently shown that aldose reductase (AR, EC 1.1.1.21) a nicotinamide adenine dinucleotide phosphate-dependent aldo-keto reductase, known to be involved in oxidative stress-signaling, prevents human colon cancer cell growth in culture as well as in nude mice xeno-grafts. Inhibition of AR also prevents azoxymethane-induced aberrant crypt foci formation in mice. In order to understand the chemopreventive mechanism(s) of AR inhibition in colon cancer, we have investigated the role of AR in the mediation of angiogenic signals in vitro and in vivo models. Our results show that inhibition of AR significantly prevented the VEGF- and FGF-induced proliferation and expression of proliferative marker Ki67 in the human umbilical vein endothelial cells (HUVEC). Further, AR inhibition or ablation with siRNA prevented the VEGF- and FGF-induced invasion and migration in HUVEC. AR inhibition also prevented the VEGF- and FGF- induced secretion/expression of IL-6, MMP2, MMP9, ICAM, and VCAM. The anti-angiogenic feature of AR inhibition in HUVEC was associated with inactivation of PI3 K/AKT and NF-κB (p65) and suppression of VEGF receptor 2 protein levels. Most importantly, matrigel plug model of angiogenesis in rats showed that inhibition of AR prevented infiltration of blood cells, invasion, migration and formation of capillary like structures, and expression of blood vessels markers CD31 and vWF. Thus, our results demonstrate that AR inhibitors could be novel agents to prevent angiogenesis.