Abstract 15330: Angiopoietin Like-2 Contributes to Cerebral Artery Endothelial Dysfunction in Mice
Introduction: Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein that is increased in CAD patients. When infused in dyslipidemic mice, it is pro-atherogenic and its overexpression targeted in endothelial cells induces aortic endothelial dysfunction. The impact of angptl2 in the cerebrovasculature, which is highly sensitive to oxidative stress, is unknown. We hypothesized that angptl2 induces cerebral artery endothelial dysfunction and, conversely, that knocking down angptl2 increases endothelial cell stress resistance.
Method/Results: We studied endothelial function by comparing acetylcholine (ACh)-mediated dilations of isolated and pressurized mouse posterior cerebral arteries. A 4-week intravenous infusion of recombinant angptl2 (8.66 ng/hr) induced endothelial dysfunction (Emax=23±3%) in 24-week-old wild-type (WT) mice compared to WT mice infused with vehicle TBSE buffer (36±2%, P<0.05; n=3-4). To test whether reduced angptl2 expression confers endothelial stress resistance, 22-week-old WT (n=10) and angptl2 knockdown (KD, n=10) littermate mice received a 2-week subcutaneous infusion of non-hypertensive pro-inflammatory and -oxidative angiotensin II (angII, 200 ng/kg/min) or saline as control. In saline-treated WT and KD mice, ACh-induced dilations were similar, but the nature of the endothelium-derived relaxing factor differed: while H2O2 contributed to dilation in WT, only NO was involved in KD mice. Furthermore, angII induced endothelial dysfunction only in WT mice (P<0.01). This was acutely reversed by either N-acetylcysteine (NAC, 10 μM), or apocynin (10 μM), suggesting that angII-induced a reversible endothelial dysfunction in WT mice related to NADPH oxidase (Nox)-dependent oxidative stress. In angII-treated KD mice, apocynin worsened vasodilation, while NAC had no effect, suggesting remodeling of the Nox systems and low oxidative stress.
Conclusion: Angptl2 induces cerebrovascular endothelial dysfunction, while reduced angptl2 expression favors NO production and increases endothelial stress resistance to angII by interfering with the Nox signaling pathway. Angptl2-dependent endothelial damage is likely the cause of its pro-atherogenic activity.
Author Disclosures: C. Yu: None. C. Martel: None. A. Raignault: None. N. Thorin-Trescases: None. E. Thorin: None.
- © 2014 by American Heart Association, Inc.