PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis

Chaoyong He, Shayna C. Medley, Taishan Hu, Myron E. Hinsdale, Florea Lupu, Renu Virmani and Lorin E. Olson ()
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Chaoyong He: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation
Shayna C. Medley: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation
Taishan Hu: Immune Cell Development and Host Defense, Fox Chase Cancer Center
Myron E. Hinsdale: University of Oklahoma Health Sciences Center
Florea Lupu: University of Oklahoma Health Sciences Center
Renu Virmani: CVPath Institute, Inc.
Lorin E. Olson: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for vascular smooth muscle cells (VSMCs). However, the direct effects of PDGF receptor β (PDGFRβ) activation on VSMCs have not been studied in the context of atherosclerosis. Here we present a new mouse model of atherosclerosis with an activating mutation in PDGFRβ. Increased PDGFRβ signalling induces chemokine secretion and leads to leukocyte accumulation in the adventitia and media of the aorta. Furthermore, PDGFRβD849V amplifies and accelerates atherosclerosis in hypercholesterolemic ApoE−/− or Ldlr−/− mice. Intriguingly, increased PDGFRβ signalling promotes advanced plaque formation at novel sites in the thoracic aorta and coronary arteries. However, deletion of the PDGFRβ-activated transcription factor STAT1 in VSMCs alleviates inflammation of the arterial wall and reduces plaque burden. These results demonstrate that PDGFRβ pathway activation has a profound effect on vascular disease and support the conclusion that inflammation in the outer arterial layers is a driving process for atherosclerosis.

Date: 2015
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DOI: 10.1038/ncomms8770

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