Pro‐atherogenic disturbed flow increases endothelial stiffness via enhanced CD36/Cav1‐ mediated oxLDL uptake

Abstract

ObjectiveDisturbed flow (DF) is known to induce endothelial dysfunction and synergistically with plasma dyslipidemia promote plaque formation. Little is known, however, about the synergistic impact of DF and dyslipidemia on endothelial biomechanical properties. Our goal was to determine the impact of DF on endothelial stiffness and evaluate the role of dyslipidemia/oxidized low density lipoprotein (oxLDL) in this process.Methods and ResultsEndothelial elastic modulus of intact mouse aortas ex vivo and of human aortic ECs (HAECs) exposed to laminar or disturbed flow in vitro was measured using atomic force microscopy. The endothelial monolayer of the aortic arch (AA) was found to be significantly stiffer than the descending aorta (DA) (4.2+1.1 vs. 2.5+0.2 kPa for AA vs. DA) in mice maintained on low fat diet (LFD). This effect was significantly exacerbated by a short‐term high‐fat diet (HFD) (8.7+2.5 vs. 4.5+1.2 kPa for AA vs. DA). Exposure of HAECs to DF in vitro resulted in a 50% increase in oxLDL uptake and significant endothelial stiffening in the presence but not in the absence of oxLDL. DF was shown to increase the expression of oxLDL receptor CD36 and the downregulation of CD36 abrogated DF‐induced endothelial oxLDL uptake and stiffening. ECs deficient in caveolin1 (Cav1) had no significant oxLDL uptake and no DF‐induced EC stiffening. Furthermore, genetic deficiencies of CD36 and of Cav1 abrogated endothelial stiffening in the aortic arch ex vivo in mice fed either LFD or HFD.ConclusionsDisturbed flow facilitates endothelial CD36/Cav1‐dependent uptake of oxidized lipids resulting in a local increase of endothelial stiffness in pro‐atherogenic areas of the aorta.Support or Funding InformationThis study is supported by NIH grants HL‐073965 (IL,DE), HL‐083298 (IL,RM,MC,PVS), and R00 HL‐103789 (YF); AHA MWA Pre‐doctoral Fellow 14PRE20490156 (EL) and the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust (DE).