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1 Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States
2 Medicine, Cardiovascular Division, University of Virginia, Charlottesville, Virginia, United States
* To whom correspondence should be addressed. E-mail: bblackman{at}virginia.edu.
Atherosclerosis is an inflammatory disease that preferentially forms at hemodynamically compromised regions of altered shear stress patterns. Endothelial (EC) and smooth muscle cells (SMC) undergo phenotypic modulation during atherosclerosis. An in vitro co-culture model was developed to determine the role of hemodynamic regulation of EC and SMC phenotype in co-culture. Human ECs and SMCs were plated on a synthetic elastic lamina and human-derived atheroprone and atheroprotective shear stresses were imposed on the ECs. Atheroprone flow decreased genes associated with differentiated ECs (eNOS, Tie2, KLF2) and SMCs (SM
Actin, myocardin) and induced a pro-inflammatory phenotype in ECs and SMCs (VCAM-1, IL-8, MCP-1). Atheroprone flow-induced changes in SMC differentiation markers were regulated at the chromatin level indicated by decreased SRF binding to the SMActin-CArG promoter region and decreased histone H4-acetylation. Conversely, SRF and H4-acetylation were enriched at the c-fos promoter in SMCs. In the presence of atheroprotective shear stresses, ECs aligned with the direction of flow and SMCs aligned more perpendicular to flow, similar to in vivo vessel organization. Results provide a novel mechanism whereby modulation of EC phenotype by hemodynamic shear stresses, atheroprone or atheroprotective, play a critical role in mechanical-transcriptional coupling and regulation of SMC phenotype.
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