Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis

Abstract

Atherosclerotic lesions develop in regions of arterial curvature and branch points, which are exposed to disturbed blood flow and have unique gene expression patterns. The cellular and molecular basis for atherosclerosis susceptibility in these regions is not completely understood. In the intima of atherosclerosis-predisposed regions of the wild-type C57BL/6 mouse aorta, we quantified increased expression of several proinflammatory genes that have been implicated in atherogenesis, including vascular cell adhesion molecule–1 (VCAM-1) and a relative abundance of dendritic cells, but only occasional T cells. In contrast, very few intimal leukocytes were detected in regions resistant to atherosclerosis; however, abundant macrophages, including T cells, were found throughout the adventitia (Adv). Considerably lower numbers of intimal CD68+ leukocytes were found in inbred atherosclerosis-resistant C3H and BALB/c mouse strains relative to C57BL/6 and 129; however, leukocyte distribution throughout the Adv of all strains was similar. The predominant mechanism for the accumulation of intimal CD68+ cells was continued recruitment of bone marrow–derived blood monocytes, suggestive of low-grade chronic inflammation. Local proliferation of intimal leukocytes was low. Intimal CD68+ leukocytes were reduced in VCAM-1–deficient mice, suggesting that mechanisms of leukocyte accumulation in the intima of normal aorta are analogous to those in atherosclerosis.

MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro

“…In the prelesion stage of normal arteries, athero-susceptible regions exhibit low-grade chronic inflammation in the intima where enhanced NF-κB activity in endothelial cells may influence the regional sensitivity for atherogenesis (7,33). In a mouse model, increased phosphorylation of IκBα in lesion-susceptible regions is consistent with preferential activation of endothelial NF-κB signaling under the systemic stimuli of hypercholesterolemia and lipopolysaccharide (7).…”

Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis – A review of the experimental evidence

“…Interestingly, this effect is more prominent at early stages of the disease while depleting monocyte/macrophages from advanced lesions does not alter plaque size or composition (13). Dendritic cells have been implicated in the formation of the earliest detectable plaques (14,15). Neutrophils are found in increased numbers in hypercholesterolemic mice and neutrophil depletion effectively reduces atherosclerosis if neutrophil-depleting antibodies are administered during early atherosclerosis development (16,17).…”

Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex

“…However, we found that its mRNA was readily detectable in the normal mouse aorta, and a reporter construct was up regulated at the inner curvature of the aortic arch that is exposed to disturbed shear stress. The subsequent chronic inflammatory activation of the endothelium in these regions "primes" the vessel for development of atherosclerosis under conditions of high cho lesterol (Jongstra Bilen et al, 2006). Deletion of VEGFR3 in adult mice reduced inflammatory signaling at this site.…”