Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

Nicolas Baeyens, Mary Jo Mulligan-Kehoe, Federico Corti, David D Simon, Tyler D Ross, John M Rhodes, Thomas Z Wang, Cecile O Mejean, Michael Simons, Jay Humphrey, Martin A Schwartz

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4(-/-)) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4(-/-) mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression of S4. This effect was highly specific, as flow activation of VEGF receptor 2 and NF-κB was normal. S4-depleted ECs aligned in cyclic stretch and even elongated under flow, although nondirectionally. EC alignment was previously found to have a causal role in modulating activation of inflammatory versus antiinflammatory pathways by flow. Consistent with these results, S4-depleted HUVECs in long-term laminar flow showed increased activation of proinflammatory NF-κB and decreased induction of antiinflammatory kruppel-like factor (KLF) 2 and KLF4. Thus, S4 plays a critical role in sensing flow direction to promote cell alignment and inhibit atherosclerosis.

    Original languageEnglish
    Pages (from-to)17308-13
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume111
    Issue number48
    DOIs
    Publication statusPublished - 2 Dec 2014

    Keywords

    • Animals
    • Atherosclerosis
    • Blotting, Western
    • Cells, Cultured
    • Endothelial Cells
    • Female
    • Human Umbilical Vein Endothelial Cells
    • Humans
    • Kruppel-Like Transcription Factors
    • Male
    • Mice, Inbred C57BL
    • Mice, Knockout
    • Microscopy, Confocal
    • NF-kappa B
    • RNA Interference
    • Reverse Transcriptase Polymerase Chain Reaction
    • Signal Transduction
    • Stress, Mechanical
    • Syndecan-4
    • Vascular Endothelial Growth Factor Receptor-2

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