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 signaling 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 signaling 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.
Highlights
Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for vascular smooth muscle cells (VSMCs)
We previously showed that a Cre-inducible gain-of-function knockin mutation in PDGF receptor b (PDGFRb) (PDGFRbD849V) induced chemokine mRNA expression in brain pericytes and caused inflammation of the central nervous system[18]
Mouse plasma contains much lower levels of chemokines compared with conditioned media, but even with this limitation we detected increased levels of circulating CCL2 and CCL3 in the plasma of PDGFRbSm22D849V mice (Fig. 1d)
Summary
PDGF signalling induces chemokine production from VSMCs. We previously showed that a Cre-inducible gain-of-function knockin mutation in PDGFRb (PDGFRbD849V) induced chemokine mRNA expression in brain pericytes and caused inflammation of the central nervous system[18]. We compared Ldlr and Ldlr,PDGFRbSm22D849V mutants after 16 weeks of WD feeding and again found a striking increase in atherosclerotic plaque area in Ldlr,PDGFRbSm22D849V aortas (Fig. 4e,f) This finding is important because ApoE itself can influence PDGFRb activity by interacting with LDL receptorrelated protein-1 (LRP1) to attenuate PDGFRb function[23,24]. (c,d) Quantification of plaque cross-sectional area at the aortic root, aortic arch, brachiocephalic artery (BCA) and thoracic aorta in mice fed WD (c) or chow diet (d) for the indicated times, n 1⁄4 10 mice of each genotype per time point; *Po0.01 by Student’s t-test for comparison between mutant and control at each time point. As discussed previously, we did not detect increased IFN (IFN-a, -b or -g) mRNA expression in PDGFRbSm22D849V VSMCs compared with control cells, consistent with the model that PDGFRb signalling is responsible for the phosphorylation of STAT1. Compared with ApoE,PDGFRbSm22D849V mutants, a much smaller area of the aorta
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