A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells

J Cell Biol. 2022 Jul 4;221(7):e202109144. doi: 10.1083/jcb.202109144. Epub 2022 Jun 13.


Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction of the anti-inflammatory transcription factor, Kruppel-like factor 2 (Klf2). We therefore performed a whole genome CRISPR-Cas9 screen to identify genes required for LSS induction of Klf2. Subsequent mechanistic investigation revealed that LSS induces Klf2 via activation of both a MEKK2/3-MEK5-ERK5 kinase module and mitochondrial metabolism. Mitochondrial calcium and ROS signaling regulate assembly of a mitophagy- and p62-dependent scaffolding complex that amplifies MEKK-MEK5-ERK5 signaling. Blocking the mitochondrial pathway in vivo reduces expression of KLF2-dependent genes such as eNOS and inhibits vascular remodeling. Failure to activate the mitochondrial pathway limits Klf2 expression in regions of disturbed flow. This work thus defines a connection between metabolism and vascular inflammation that provides a new framework for understanding and developing treatments for vascular disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Atherosclerosis / pathology
  • CRISPR-Cas Systems
  • Calcium Signaling
  • Endothelial Cells* / metabolism
  • Humans
  • Inflammation
  • Kruppel-Like Transcription Factors* / genetics
  • Kruppel-Like Transcription Factors* / metabolism
  • MAP Kinase Kinase 5
  • MAP Kinase Kinase Kinase 2
  • MAP Kinase Kinase Kinase 3
  • Mitochondria* / metabolism
  • Mitogen-Activated Protein Kinase 7 / genetics
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Reactive Oxygen Species
  • Stress, Mechanical*


  • KLF2 protein, human
  • Kruppel-Like Transcription Factors
  • Reactive Oxygen Species
  • Mitogen-Activated Protein Kinase 7
  • MAP Kinase Kinase Kinase 2
  • MAP Kinase Kinase Kinase 3
  • MAP3K2 protein, human
  • MAP3K3 protein, human
  • MAP Kinase Kinase 5
  • MAP2K5 protein, human