Mechanoregulation of p38 activity enhances endoplasmic reticulum stress-mediated inflammation by arterial endothelium

Keith A. Bailey, Emily Moreno, Fawaz G. Haj, Scott I Simon, Anthony G. Passerini

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Endothelial up-regulation of VCAM-1 at susceptible sites in arteries modulates the recruitment efficiency of inflammatory monocytes that initiates atherosclerotic lesion formation. We reported that hydrodynamic shear stress (SS) mechanoregulates inflammation in human aortic endothelial cells through endoplasmic reticulum (ER) stress via activation of the transcription factor x-box binding protein 1 (XBP1). Here, a microfluidic flow channel that produces a linear gradient of SS along a continuous monolayer of endothelium was used to delve the mechanisms underlying transcriptional regulation of TNF-α-stimulated VCAM-1 expression. High-resolution immunofluorescence imaging enabled continuous detection of platelet endothelial cell adhesion molecule 1 (PECAM-1)-dependent, outside-in signaling as a function of SS magnitude. Differential expression of VCAM-1 and intercellular adhesion molecule 1 (ICAM-1) was regulated by the spatiotemporal activation of MAPKs, ER stress markers, and transcription factors, which was dependent on the mechanosensing of SS through PECAM-1 and PI3K. Inhibition of p38 specifically abrogated the rise to peak VCAM-1 at low SS (2 dyn/cm2), whereas inhibition of ERK1/2 attenuated peak ICAM-1 at high SS (12 dyn/cm2). A shear stress-regulated temporal rise in p38 phosphorylation activated the nuclear translocation of XBP1, which together with the transcription factor IFN regulatory factor 1, promoted maximum VCAM-1 expression. These data reveal a mechanism by which SS sensitizes the endothelium to a cytokine-induced ER stress response to spatially regulate inflammation promoting atherosclerosis.-Bailey, K. A., Moreno, E., Haj, F. G., Simon, S. I., Passerini, A. G. Mechanoregulation of p38 activity enhances endoplasmic reticulum stress-mediated inflammation by arterial endothelium.

Original languageEnglish (US)
Pages (from-to)12888-12899
Number of pages12
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number11
DOIs
StatePublished - Nov 1 2019

Keywords

  • atherosclerosis
  • MAPK
  • mechanotransduction
  • shear stress
  • VCAM-1

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Mechanoregulation of p38 activity enhances endoplasmic reticulum stress-mediated inflammation by arterial endothelium'. Together they form a unique fingerprint.

  • Cite this