Atherosclerosis-prone hemodynamics differentially regulates endothelial and smooth muscle cell phenotypes and promotes pro-inflammatory priming

Nicole E. Hastings, Michael B. Simmers, Oliver G. McDonald, Brian R. Wamhoff, Brett R. Blackman

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

Atherosclerosis is an inflammatory disease that preferentially forms at hemodynamically compromised regions of altered shear stress patterns. Endothelial cells (EC) and smooth muscle cells (SMC) undergo phenotypic modulation during atherosclerosis. An in vitro coculture model was developed to determine the role of hemodynamic regulation of EC and SMC phenotypes in coculture. Human ECs and SMCs were plated on a synthetic elastic lamina and human-derived atheroprone, and atheroprotective shear stresses were imposed on ECs. Atheroprone flow decreased genes associated with differentiated ECs (endothelial nitric oxide synthase, Tie2, and Kruppel-like factor 2) and SMCs (smooth muscle α-actin and myocardin) and induced a proinflammatory phenotype in ECs and SMCs (VCAM-1, IL-8, and monocyte chemoattractant protein-1). Atheroprone flow-induced changes in SMC differentiation markers were regulated at the chromatin level, as indicated by decreased serum response factor (SRF) binding to the smooth muscle α-actin-CC(a/T)6GG (CArG) promoter region and decreased histone H4 acetylation. Conversely, SRF and histone 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. These results provide a novel mechanism whereby modulation of the EC phenotype by hemodynamic shear stresses, atheroprone or atheroprotective, play a critical role in mechanical- transcriptional coupling and regulation of the SMC phenotype.

Original languageEnglish (US)
Pages (from-to)C1824-C1833
JournalAmerican Journal of Physiology - Cell Physiology
Volume293
Issue number6
DOIs
StatePublished - Dec 2007
Externally publishedYes

Keywords

  • Coculture
  • Endothelial cells
  • Phenotypic modulation
  • Shear stress
  • Smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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