Critical Role of Macrophages in Glucocorticoid Driven Vascular Calcification in a Mouse-Model of Atherosclerosis

Abstract

Objective-Macrophage-derived products are known to play a crucial role during atherogenesis and vascular calcification.Glucocorticoids (GC) are important modulators of immune cell functions, but their specific effects on macrophages behavior during plaque formation are not defined. The present study was therefore designed to investigate the effects of macrophage-specific deletion of the glucocorticoid receptor (GR LysMCre ) on atherogenesis and vascular calcification in a hyperlipidemic mouse-model. Methods and Results-Bone marrow was isolated from GRLysMCre mice and wild-type controls (GR flox ) and subsequently transplanted into lethally irradiated LDL-receptor-deficient mice. Animals were fed a Western-type diet for 15 or 24 weeks, and atherosclerotic lesions within the aortic sinus were evaluated. At both time points, no significant difference in serum lipid and corticosterone concentrations, atherosclerotic lesion size and macrophage-content within the lesions could be observed. However, GR LysMCre mice showed less calcification as well as a significant reduction of RANKL, BMP2, and Msx2 expression within the vasculature. In vitro studies using conditioned media from macrophages which had been stimulated with dexamethasone demonstrated a dose-dependent increase in calcium deposition by vascular smooth muscle cells. Conclusion-This

Ultrastructure of Apatite Crystals Formed During Vascular Calcification in Humans

“…2a) after the death of cells, as in the case of dental calculus, and the envelope structure is regarded as a prerequisite for the formation of crystals in calcified hard tissues 24-26, 31, 32) . Extrapolating from the present results, and given the circumstances under which inflammatory events occur 6,9,17,[40][41][42] , cellular debris plausibly originates from the degeneration of immune-related cells as well as perivascular cells. In particular, macrophages seem to be a prime candidate after their death.…”

“…The causes and mechanisms of ectopic calcification, however, have not been fully elucidated as yet. As a result, pathological calcification, such as vascular calcification and fibrodysplasia ossificans progressiva, may be regulated by many possible contributing factors, and may occur in the same manner as bone calcification occurs after the conversion of soft tissue to hard tissue-forming cells, namely, osteoblasts or osteoblast-like cells [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . Thus, mainly on the basis of in vitro results, differentiation of soft tissue into hard tissueforming cells is considered to be the primary cause of ectopic calcification.…”

Molecular Biology of Atherosclerosis

“…GR BMT of macrophagespecific GR Ϫ/Ϫ into LDLR Ϫ/Ϫ NS GR (glucocorticoid receptor) deficiency in macrophages did not affect lesion size but did decrease lesion calcification (1437).…”

Corticosteroid receptors, macrophages and cardiovascular disease

“…A role for macrophage GR signalling in a model of atherosclerosis has recently been identified by transplanting bone marrow derived from macrophage GR-null mice into LDL receptor deficient mice (Preusch et al 2008). Interestingly, deletion of GR from macrophages had no effect on atherosclerotic lesion size or macrophage number, suggesting that the effects of glucocorticoids on atherosclerosis are only partially mediated through GR.…”