Biomechanical regulation of endothelium-dependent events critical for adaptive remodeling

Peter J. Mack, Yuzhi Zhang, Seok Chung, Vernella Vickerman, Roger D. Kamm, Guillermo García-Cardeña

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Alterations in hemodynamic shear stress acting on the vascular endothelium are critical for adaptive arterial remodeling. The molecular mechanisms regulating this process, however, remain largely uncharacterized. Here, we sought to define the responses evoked in endothelial cells exposed to shear stress waveforms characteristic of coronary collateral vessels and the subsequent paracrine effects on smooth muscle cells. Alumped parameter model of the human coronary collateral circulation was used to simulate normal and adaptive remodeling coronary collateral shear stress waveforms. These wave forms were then applied to cultured human endothelial cells (EC), and the resulting differences in EC gene expression were assessed by genome-wide transcriptional profiling to identify genes distinctly regulated by collateral flow. Analysis of these transcriptional programs identified several genes to be differentially regulated by collateral flow, including genes important for endothelium-smooth muscle interactions. In particular, the transcription factor KLF2 was up-regulated by the adaptive remodeling coronary collateral waveform, and several of its downstream targets displayed the expected modulation, including the down-regulation of connective tissue growth factor. To assess the effect of endothelial KLF2 expression on smooth muscle cell migration, a three-dimensional microfluidic assay was developed. Using this three-dimensional system, we showed that KLF2-expressing EC co-cultured with SMC significantly reduce SMC migration compared with control EC and that this reduction can be rescued by the addition of exogenous connective tissue growth factor. Collectively, these results demonstrate that collateral flow evokes distinct EC gene expression profiles and functional phenotypes that subsequently influence vascular events important for adaptive remodeling.

Original languageEnglish
Pages (from-to)8412-8420
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number13
DOIs
Publication statusPublished - 2009 Mar 27
Externally publishedYes

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Endothelial cells
Endothelium
Endothelial Cells
Genes
Connective Tissue Growth Factor
Muscle
Shear stress
Gene expression
Smooth Muscle Myocytes
Cells
Coronary Circulation
Collateral Circulation
Microfluidics
Gene Flow
Vascular Endothelium
Hemodynamics
Transcriptome
Cell Movement
Smooth Muscle
Blood Vessels

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Biomechanical regulation of endothelium-dependent events critical for adaptive remodeling. / Mack, Peter J.; Zhang, Yuzhi; Chung, Seok; Vickerman, Vernella; Kamm, Roger D.; García-Cardeña, Guillermo.

In: Journal of Biological Chemistry, Vol. 284, No. 13, 27.03.2009, p. 8412-8420.

Research output: Contribution to journalArticle

Mack, Peter J. ; Zhang, Yuzhi ; Chung, Seok ; Vickerman, Vernella ; Kamm, Roger D. ; García-Cardeña, Guillermo. / Biomechanical regulation of endothelium-dependent events critical for adaptive remodeling. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 13. pp. 8412-8420.
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