Abstract 12275: Knock-down of Insulin-like Growth Factor-1 Receptor in the Endothelium Decreases Anti-oxidant Capacity of Aorta, Leading to Increased Atherosclerosis

Abstract

Systemic infusion of insulin-like growth factor-1 (IGF-1) in Apoe-deficient mice exerts anti-atherogenic effects by reducing oxidative stress and pro-inflammatory responses in lesions, yet precise mechanisms remain elusive. We have shown that smooth muscle specific IGF-1 overexpression does not reduce atherosclerotic burden, suggesting that smooth muscle cells do not mediate anti-atherogenic effects of IGF-1. The endothelium is integral in atherogenesis, however a potential role of endothelial IGF-1 receptor (IGF1R) signaling in atherogenesis is unknown. To investigate, we generated Apoe-deficient/endothelial IGF1R-knockdown (En-IGF1R-KD) mice, which are Igf1r-floxed and express Cre recombinase driven by the Cdh5-promoter. IGF1R expression levels were lower by 60% in endothelial cells isolated from En-IGF1R-KD mice compared to IGF1R-flox cells. After 12 weeks of high-fat diet feeding, En-IGF1R-KD mice had more atherosclerotic plaque than IGF1R-flox control (Oil Red O staining of en face aorta, 33±8% increase, P<0.05), indicating that loss of endothelial IGF1R signaling enhanced atherogenesis. Intriguingly, En-IGF1R-KD did not alter systolic blood pressure (IGF1R-flox; 119.5±2.6 vs. En-IGF1R-KD; 119.1±2.0 mmHg) or plasma nitrate/nitrite levels (index of nitric oxide bioavailability, IGF1R-flox; 8.6±0.4 vs. En-IGF1R-KD; 7.3±0.9 uM). Vasorelaxation to acetylcholine (Ach) was equivalent in aortas of En-IGF1R-KD and IGF1R-flox mice after high-fat diet feeding, suggesting that endothelial function was not affected by En-IGF1R-KD. Intriguingly, high-fat diet feeding made aortas hyporesponsive to Ach both in En-IGF1R-KD and IGF1R-flox mice, and in normal chow fed mice En-IGF1R-KD aortas were more responsive to Ach than IGF1R-flox aortas, indicating that loss of IGF-1 signaling improved endothelial function. On the other hand, anti-oxidant capacity as measured by Hydroxyl Radical Antioxidant Capacity Activity Assay was significantly lower in En-IGF1R-KD aorta by 30.0±6.7%, consistent with anti-oxidant effects of IGF-1 on endothelial cells. In summary, our results indicate that IGF1R signaling in the endothelium is atheroprotective, and that this atheroprotective effect is mediated via an anti-oxidant mechanism.