| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Simons, Michael Ross, Tyler D. Wang, Thomas Z. Rhodes, John M. Baeyens, Nicolas Mejean, Cecile O. Schwartz, Martin A. Corti, Federico Humphrey, Jay Mulligan-kehoe, Mary Jo Simon, David D. |
| Description |
Author Affiliation: Baeyens N ( Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520); Mulligan-Kehoe MJ ( Department of Surgery, Vascular Section, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766); Corti F ( Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520); Simon DD ( Department of Biomedical Engineering, Yale University, New Haven, CT 06520); Ross TD ( Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520); Rhodes JM ( Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520); Wang TZ ( Department of Surgery, Vascular Section, Geisel School of Medicine at Dartmouth, Lebanon, NH 03766); Mejean CO ( Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520); Simons M ( Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520); Humphrey J ( Department of Biomedical Engineering, Yale University, New Haven, CT 06520); Schwartz MA ( Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, New Haven, CT 06520); |
| 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. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
48 |
| Volume Number |
111 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2014-12-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Atherosclerosis Metabolism Endothelial Cells Signal Transduction Syndecan-4 Animals Genetics Blotting, Western Cells, Cultured Cytology Human Umbilical Vein Endothelial Cells Kruppel-Like Transcription Factors Mice, Inbred C57BL Mice, Knockout Microscopy, Confocal NF-kappa B RNA Interference Reverse Transcriptase Polymerase Chain Reaction Stress, Mechanical Vascular Endothelial Growth Factor Receptor-2 Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
