Angiopoietin like-2: a pro-inflammatory and pro-oxidative protein that contributes to endothelial dysfunction

Vascular aging is characterized by changes in the endothelium. Common cardiovascular risk factors, including obesity and hypertension, predispose the endothelium to increased oxidative stress, leading to endothelial dysfunction commonly characterized by diminished nitric oxide bioavailability. Although endothelial function can be a major determinant of cardiovascular risk prediction in patients, individual testing is still limited in clinical settings and thus there is increasing scientific interest in finding better biomarkers.  Angiopoietin like-2 (angptl2), a recently identified protein, is a pro-inflammatory and pro-oxidative protein involved in chronic inflammatory disorders ranging from obesity to atherosclerosis. As inflammation and increased oxidative stress are established underlying mechanisms by which endothelial dysfunction occurs, this work focuses on the role of angptl2 in endothelial dysfunction, a topic that is largely unexplored. Specifically, this work aims to 1) determine the acute effects of angptl2 on endothelial function, 2) characterize endothelial function and contribution of different endothelium-derived relaxing factors in various vascular beds in a newly generated angptl2 knock-down (KD) mouse model, and 3) examine whether the lack of angptl2 expression protects against endothelial dysfunction induced by either a high-fat diet (HFD) or angiotensin II (angII) infusion in mice. In the first study, we show that a recombinant angptl2 acutely evokes endothelial dysfunction in the femoral artery isolated from wild-type (WT) mice, likely due to increased production of reactive oxygen species. Also in the femoral artery, angptl2 KD mice display better endothelial function compared to WT, which may be a result of greater prostacyclin contribution to vasodilation. After a 3-month HFD, the main respective endothelium-derived relaxing factors in the femoral and mesenteric arteries are preserved in angptl2 KD mice only, which was associated with a better metabolic profile, such as lower total cholesterol-to-high-density lipoprotein and low-density-to-high-density lipoprotein ratios compared to WT mice. After a HFD, KD mice have less triglyceride accumulation in the liver and smaller adipocytes in their mesenteric and epididymal white adipose tissues compared to WT mice, while inflammatory gene expressions in adipose tissues increase in WT mice only.  In the second study, we reveal that the lack of angptl2 in KD mice results in greater nitric oxide production compared to WT mice in their isolated cerebral arteries. Chronic infusion of pro-inflammatory and pro-oxidative angII results in cerebral endothelial dysfunction only in WT mice, which is acutely ameliorated with either N-acetylcysteine, apocynin, or indomethacin, suggesting increased reactive oxygen species, likely derived from the NADPH oxidases 1/2, and increased cyclooxygenase-derived endothelium-derived contracting factors. In contrast, apocynin reduces cerebral dilation in angII-treated KD mice, suggesting recruitment of a potential compensatory dilatory NADPH oxidase pathway. These studies are the first to explore angptl2 contribution to endothelial dysfunction in different vascular beds, and strongly suggest that angptl2 can directly impair endothelial function by its pro-inflammatory and pro-oxidative properties. Translating this to the clinical setting, expression levels of angptl2 may be an indicator of endothelial function, and lowering angptl2 levels could become a potential therapeutic approach in the treatment of chronic inflammatory disorders including cardiovascular diseases.

Keyphrases: Angiopoietin like-2, Endothelium-derived relaxing factors, Obesity, Angiotensin II, NADPH oxidase, Reactive oxygen species, Obésité