Syk/PECAM-1 Signaling Pathway Mediates Low Shear Stress-Induced Inflammatory in Atherosclerosis

Abstract

Although blood flow shear stress has been demonstrated to alter the physiology of vascular endothelial cells, little is known about the role of Syk in PECAM-1 signaling pathway exposed to low shear stress (LSS). Methods: In vitro, primary human umbilical vein endothelial cells (HUVECs) were stimulated with parallel plate flow chamber system for 12h under normal shear stress (NSS, 15dyne/cm2), LSS (5dyne/cm2) and high shear stress (HSS, 25dyne/cm2), respectively, followed by inflammatory response analysis. In vivo, atherosclerotic animal models of rat and rabbit were created by feeding with high cholesterol diets. The animals were applied with LSS stimulation by constricting left carotid artery with a blunted needle (0.8mm in diameter). Small molecule R406, a well-demonstrated Syk inhibitor, was applied to the atherosclerotic animal models as well as HUVEC cells. Results: LSS influenced carotid atherosclerosis in the LSS model of rabbits; LSS promoted expression of PECAM-1 and Syk in LSS-treated atherosclerotic rat model; LSS influenced the morphology of abdominal aortic endothelial cells in rats; LSS increased the expression of pPECAM-1, Syk and NF-κB in HUVECs, and inhibition of Syk attenuated LSSinduced inflammatory response. Conclusion: Activation of spleen tyrosine kinase (Syk)/platelet endothelial cell adhesion molecule-1(PECAM-1) signaling pathway was accompanied with inflammatory response induced by LSS stimulation both in vitro and in vivo. This work demonstrated the important role Syk/PECAM1/NF-κB signaling pathway plays in LSS-induced inflammatory response. Funding Statement: This work was supported by Pudong New Area Health Bureau of Shanghai (grant no.PWZbr2017-09), and the National Natural Science Foundation of China (grant no.81401428, 81571693 and 81871361). Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: Human umbilical vein from normal full-term newborns was obtained with informed consent and approved in accordance with the procedures of the Medical Ethics Committee of Shanghai East Hospital Affiliated to Tongji University (China).