Cells (Jul 2021)

A Switch from Cell-Associated to Soluble PDGF-B Protects against Atherosclerosis, despite Driving Extramedullary Hematopoiesis

  • Renée J. H. A. Tillie,
  • Thomas L. Theelen,
  • Kim van Kuijk,
  • Lieve Temmerman,
  • Jenny de Bruijn,
  • Marion Gijbels,
  • Christer Betsholtz,
  • Erik A. L. Biessen,
  • Judith C. Sluimer

DOI
https://doi.org/10.3390/cells10071746
Journal volume & issue
Vol. 10, no. 7
p. 1746

Abstract

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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.

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