Desensitization of Platelet-Derived Growth Factor Receptor-β by Oxidized Lipids in Vascular Cells and Atherosclerotic Lesions

Abstract

The platelet-derived growth factor receptor-β (PDGFRβ) signaling pathway regulates smooth muscle cell (SMC) migration and proliferation and plays a role in the vascular wall response to injury. Oxidized low-density lipoprotein (oxLDL) in atherosclerotic lesions can activate the PDGFRβ pathway, but the long-term effects of oxLDL on PDGFRβ function are not well understood. We found that oxLDL induced a dual effect on PDGFRβ signaling. Initial activation of the PDGFR was followed by desensitization of the receptor. PDGFRβ desensitization was not attributable to PDGFRβ degradation or changes in localization to the caveolae but instead resulted from decreased PDGF binding and inhibition of PDGFRβ tyrosine kinase activity. This inhibition was associated with formation of (4HNE)– and acrolein–PDGFRβ adducts and was mimicked by preincubation of cells with 4HNE. These PDGFRβ adducts were also detected in aortae of apolipoprotein-deficient mice and hypercholesterolemic rabbits and in human carotid plaques. The aldehyde scavengers DNPH and Hydralazine prevented both oxLDL- and 4HNE-induced structural modification and PDGFRβ signaling dysfunction in cells and in vivo. OxLDL inhibition of PDGF signaling may contribute to defective SMC proliferation and decrease the stability of a vulnerable plaque.