Abstract
Platelet-derived growth factor B (PDGF-B) is a mitogenic, migratory and survival factor. Cell-associated PDGF-B recruits stabilizing pericytes towards blood vessels through retention in extracellular matrix. We hypothesized that the genetic ablation of cell-associated PDGF-B by retention motif deletion would reduce the local availability of PDGF-B, resulting in microvascular pericyte loss, microvascular permeability and exacerbated atherosclerosis. Therefore, Ldlr-/-Pdgfbret/ret mice were fed a high cholesterol diet. Although plaque size was increased in the aortic root of Pdgfbret/ret mice, microvessel density and intraplaque hemorrhage were unexpectedly unaffected. Plaque macrophage content was reduced, which is likely attributable to increased apoptosis, as judged by increased TUNEL+ cells in Pdgfbret/ret plaques (2.1-fold) and increased Pdgfbret/ret macrophage apoptosis upon 7-ketocholesterol or oxidized LDL incubation in vitro. Moreover, Pdgfbret/ret plaque collagen content increased independent of mesenchymal cell density. The decreased macrophage matrix metalloproteinase activity could partly explain Pdgfbret/ret collagen content. In addition to the beneficial vascular effects, we observed reduced body weight gain related to smaller fat deposition in Pdgfbret/ret liver and adipose tissue. While dampening plaque inflammation, Pdgfbret/ret paradoxically induced systemic leukocytosis. The increased incorporation of 5-ethynyl-2′-deoxyuridine indicated increased extramedullary hematopoiesis and the increased proliferation of circulating leukocytes. We concluded that Pdgfbret/ret confers vascular and metabolic effects, which appeared to be protective against diet-induced cardiovascular burden. These effects were unrelated to arterial mesenchymal cell content or adventitial microvessel density and leakage. In contrast, the deletion drives splenic hematopoiesis and subsequent leukocytosis in hypercholesterolemia.
Highlights
IntroductionThe normal artery wall consists of three layers: the intima, the medial layer and the adventitia from luminal inside to outside, respectively [1]
Platelet-derived growth factor B (PDGF-B) immunoreactivity was present in macrophages and endothelial cells (ECs), which is in line with mRNA expression in these cell types in vitro (Figure 1A,B)
In order to further investigate the decreased Pdgfbret/ret plaque macrophage content and its possible association with increased plaque collagen content, we studied whether the Pdgfbret/ret macrophage function was affected
Summary
The normal artery wall consists of three layers: the intima, the medial layer and the adventitia from luminal inside to outside, respectively [1]. The adventitia harbors connective tissue, mesenchymal cells (MCs), immune cells and blood vessels amongst others [1]. Atherosclerosis is characterized by plaque accumulation in the subendothelial space of the intimal layer [1]. Plaque rupture and subsequent luminal thrombus formation can cause lifethreatening complications [3]. The switch from plaques with stabilizing features, such as high mesenchymal cell density and resulting collagen accumulation and a thick fibrous cap, is triggered by the accumulation of immune cells, apoptosis and angiogenesis [4]
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