Macrophage Glucocorticoid Receptors Join the Intercellular Dialogue in Atherosclerotic Lesion Calcification

Abstract

Arterial calcification is one of the potential phenotypes of vascular remodeling and repair in atherosclerosis, diabetes, hyperphosphatemic renal failure, and aging.1–3 Calcification decreases arterial wall compliance.4 Furthermore, deposited crystalline apatite can activate macrophages, resulting in a proinflammatory phenotype. Consequently, arterial calcification localized to the intima is a potential biomarker of atherosclerosis and is linked to disease progression and cardiovascular mortality, whereas arterial calcification localized primarily to the tunica media promotes mortality in diabetes and renal failure.4 In addition, calcific stenosis of the aortic valve is a prevalent and highly significant public health problem, and shares such pathophysiological features as ectopic chondro-osseous differentiation in common with arterial calcification.5 See accompanying article on page 2158 In a study published in the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Preusch et al report the effects of lineage-specific deletion of the glucocorticoid receptor (GR) in bone marrow-donor macrophages on chondro-osseous differentiation and calcification in dietary-induced atherosclerotic lesions in lethally irradiated, bone marrow transplant recipient, LDLR knockout mice.6 Arterial calcification appears to be an active and organized multicellular process, which is switched on by chondro-osseous differentiation of a variety of progenitors in the artery wall, and regulated in part by systemic influences. Such influences include the effects of calciotropic hormones and of mineral nucleation promoters and inhibitors.1–4 In the intralesional intercellular dialogue that drives vascular calcification, potential progenitors of calcifying osteoblastic and chondrocytic cells include not only pericytes and resident and recruited vascular stem cells, but also nonterminally differentiated phenotypically plastic adventitial myofibroblasts and smooth muscle cells (SMCs). Significantly, the latter may undergo chondro-osseous transdifferentiation.1–5,7–12 Intralesional mechanisms that drive chondro-osseous differentiation in arterial calcification include an excess of inducers of chondro-osseous …