title: PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis.
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, PDGFRβ(D849V) 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.
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, 825 North East 13th Street, Oklahoma City, Oklahoma 73013, USA.
authors.forename: Chaoyong
authors.initials: C
authors.lastname: He
authors.affiliation: 1] Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, 825 North East 13th Street, Oklahoma City, Oklahoma 73013, USA [2] Department of Cell Biology, University of Oklahoma Health Sciences Center, 1100 North Lindsay Avenue, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Shayna C
authors.initials: SC
authors.lastname: Medley
authors.affiliation: Immune Cell Development and Host Defense, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Taishan
authors.initials: T
authors.lastname: Hu
authors.affiliation: 1] Department of Cell Biology, University of Oklahoma Health Sciences Center, 1100 North Lindsay Avenue, Oklahoma City, Oklahoma 73104, USA [2] Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74074, USA.
authors.forename: Myron E
authors.initials: ME
authors.lastname: Hinsdale
authors.affiliation: 1] Department of Cell Biology, University of Oklahoma Health Sciences Center, 1100 North Lindsay Avenue, Oklahoma City, Oklahoma 73104, USA [2] Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 North East 13th Street, Oklahoma City, Oklahoma 73013, USA.
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.affiliation: CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, Maryland 20878, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.affiliation: 1] Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, 825 North East 13th Street, Oklahoma City, Oklahoma 73013, USA [2] Department of Cell Biology, University of Oklahoma Health Sciences Center, 1100 North Lindsay Avenue, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Lorin E
authors.initials: LE
authors.lastname: Olson
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D018925:Chemokines / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism; D047468:Immunoprecipitation; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009131:Muscle, Smooth, Vascular; D032389:Myocytes, Smooth Muscle; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D018925:Chemokines; D011973:Receptors, LDL; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014280:Triglycerides; D002784:Cholesterol; D020797:Receptor, Platelet-Derived Growth Factor beta