title: Reduced macrophage-dependent inflammation improves endothelin-1-induced vascular injury.
abstract: Transgenic mice with endothelium-specific endothelin-1 (ET-1) overexpression exhibit endothelial dysfunction and vascular remodeling, oxidative stress, and inflammation. We previously observed that monocytes/macrophages play a role in angiotensin II, aldosterone, and deoxycorticosterone acetate/salt-induced vascular remodeling, oxidative stress, and inflammation using a model with reduced monocytes/macrophages, the osteopetrotic (Op) mouse, which has a mutation in the macrophage colony stimulating factor (Csf1) gene. However, it is unknown whether monocytes/macrophages are implicated in adverse vascular effects of ET-1. We hypothesized that reduction in monocytes/macrophages would blunt ET-1-induced vascular injury. We performed a study on 4- to 6-month-old male mice with endothelium-specific ET-1 overexpression (eET-1), reduction in CSF1 (Csf1(Op/+)), or both (eET-1/Csf1(Op/+)), and their wild-type littermate control mice. There was no difference in systolic blood pressure between groups. Endothelial function and vascular structure were determined on a pressurized myograph. Endothelium-dependent relaxation in response to acetylcholine was similar in eET-1 and eET-1/Csf1(Op/+) mice. Media:lumen ratio and media cross-sectional area were ≈1.5-fold greater in eET-1 than in wild-type mice (P<0.05), which was not observed in mice deficient in CSF1. ET-1-induced oxidative stress measured by dihydroethidium staining (P<0.05) and NADPH oxidase activity assessed with lucigenin chemiluminescence (P<0.05) were blunted by CSF1 deficiency. ET-1 caused a 2.5-fold increase in monocyte/macrophage infiltration compared with wild-type mice (P<0.001), which was blunted in the mice deficient in CSF1. Reduction of monocyte/macrophage-dependent inflammation in mice overexpressing ET-1 in endothelium results in reduced vascular remodeling and oxidative stress, providing evidence for a role of monocytes/macrophages and innate immunity in ET-1-induced vascular injury.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Danesh
authors.initials: D
authors.lastname: Javeshghani
authors.forename: Tlili
authors.initials: T
authors.lastname: Barhoumi
authors.forename: Nourredine
authors.initials: N
authors.lastname: Idris-Khodja
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D016133:Polymerase Chain Reaction; D057772:Vascular System Injuries / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D019332:Endothelin-1; D016173:Macrophage Colony-Stimulating Factor; D004247:DNA
keywords: CSF1; innate immunity; macrophage colony stimulating factor; monocytes; osteopetrosis mutation; oxidative stress; vascular remodeling