Loss of Jak2 impairs endothelial function by attenuating Raf-1/MEK1/Sp-1 signaling along with altered eNOS activities

Am J Pathol. 2013 Aug;183(2):617-25. doi: 10.1016/j.ajpath.2013.04.007. Epub 2013 Jun 6.


A number of inhibitors have been used to dissect the functional relevance of Jak2 in endothelial homeostasis, with disparate results. Given that Jak2 deficiency leads to embryonic lethality, the exact role of Jak2 in the regulation of postnatal endothelial function is yet to be fully elucidated. We generated a model in which Jak2 deficiency can be induced by tamoxifen in adult mice. Loss of Jak2 significantly impaired endothelium-dependent response capacity for vasodilators. Matrigel plug assays indicated a notable decrease in endothelial angiogenic function in Jak2-deficient mice. Studies in a hindlimb ischemic model indicated that Jak2 activity is likely to be a prerequisite for prompt perfusion recovery, based on the concordance of temporal changes in Jak2 expression during the course of ischemic injury and perfusion recovery. A remarkable delay in perfusion recovery, along with reduced capillary and arteriole formation, was observed in Jak2-deficient mice. Antibody array studies indicated that loss of Jak2 led to repressed eNOS expression. In mechanistic studies, Jak2 deficiency attenuated Raf-1/MEK1 signaling, which then reduced activity of Sp-1, an essential transcription factor responsible for eNOS expression. These data are important not only for understanding the exact role that Jak2 plays in endothelial homeostasis, but also for assessing Jak2-based therapeutic strategies in a variety of clinical settings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / enzymology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / physiology
  • Enzyme Inhibitors / pharmacology
  • Hindlimb / blood supply
  • Ischemia / enzymology
  • Janus Kinase 2 / deficiency*
  • Janus Kinase 2 / drug effects
  • MAP Kinase Kinase 1 / physiology*
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nitric Oxide Synthase Type III / metabolism*
  • Protein Kinases / physiology*
  • Proto-Oncogene Proteins c-raf / physiology*
  • Tamoxifen / pharmacology
  • Vasodilator Agents / pharmacology


  • Enzyme Inhibitors
  • Vasodilator Agents
  • Tamoxifen
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Protein Kinases
  • Sp1 kinase
  • Janus Kinase 2
  • Proto-Oncogene Proteins c-raf
  • MAP Kinase Kinase 1