Atherosusceptible Shear Stress Activates Endoplasmic Reticulum Stress to Promote Endothelial Inflammation

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Atherosclerosis impacts arteries where disturbed blood flow renders the endothelium susceptible to inflammation. Cytokine activation of endothelial cells (EC) upregulates VCAM-1 receptors that target monocyte recruitment to atherosusceptible regions. Endoplasmic reticulum (ER) stress elicits EC dysregulation in metabolic syndrome. We hypothesized that ER plays a central role in mechanosensing of atherosusceptible shear stress (SS) by signaling enhanced inflammation. Aortic EC were stimulated with low-dose TNFα (0.3 ng/ml) in a microfluidic channel that produced a linear SS gradient over a 20mm field ranging from 0-16 dynes/cm2. High-resolution imaging of immunofluorescence along the monolayer provided a continuous spatial metric of EC orientation, markers of ER stress, VCAM-1 and ICAM-1 expression, and monocyte recruitment. VCAM-1 peaked at 2 dynes/cm2 and decreased to below static TNFα-stimulated levels at atheroprotective-SS of 12 dynes/cm2, whereas ICAM-1 rose to a maximum in parallel with SS. ER expansion and activation of the unfolded protein response also peaked at 2 dynes/cm2, where IRF-1-regulated VCAM-1 expression and monocyte recruitment also rose to a maximum. Silencing of PECAM-1 or key ER stress genes abrogated SS regulation of VCAM-1 transcription and monocyte recruitment. We report a novel role for ER stress in mechanoregulation at arterial regions of atherosusceptible-SS inflamed by low-dose TNFα.

Original languageEnglish (US)
Article number8196
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Endoplasmic Reticulum Stress
Vascular Cell Adhesion Molecule-1
Monocytes
Inflammation
Endothelial Cells
Intercellular Adhesion Molecule-1
Endoplasmic Reticulum
CD31 Antigens
Unfolded Protein Response
Microfluidics
Endothelium
Fluorescent Antibody Technique
Atherosclerosis
Up-Regulation
Arteries
Cytokines
Genes

ASJC Scopus subject areas

  • General

Cite this

Atherosusceptible Shear Stress Activates Endoplasmic Reticulum Stress to Promote Endothelial Inflammation. / Bailey, Keith A.; Haj, Fawaz; Simon, Scott I.; Passerini, Anthony G.

In: Scientific Reports, Vol. 7, No. 1, 8196, 01.12.2017.

Research output: Contribution to journalArticle

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