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

Ping Yang, Yawen Zhang, Junfeng Pang, Shu Zhang, Qilin Yu, Long He, Kay Uwe Wagner, Zhiguang Zhou, Cong Yi Wang

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)617-625
Number of pages9
JournalAmerican Journal of Pathology
Volume183
Issue number2
DOIs
StatePublished - Aug 1 2013

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Perfusion
Homeostasis
Arterioles
Tamoxifen
Hindlimb
Vasodilator Agents
Endothelium
Transcription Factors
Antibodies
Wounds and Injuries
Therapeutics
matrigel

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Loss of Jak2 impairs endothelial function by attenuating Raf-1/MEK1/Sp-1 signaling along with altered eNOS activities. / Yang, Ping; Zhang, Yawen; Pang, Junfeng; Zhang, Shu; Yu, Qilin; He, Long; Wagner, Kay Uwe; Zhou, Zhiguang; Wang, Cong Yi.

In: American Journal of Pathology, Vol. 183, No. 2, 01.08.2013, p. 617-625.

Research output: Contribution to journalArticle

Yang, Ping ; Zhang, Yawen ; Pang, Junfeng ; Zhang, Shu ; Yu, Qilin ; He, Long ; Wagner, Kay Uwe ; Zhou, Zhiguang ; Wang, Cong Yi. / Loss of Jak2 impairs endothelial function by attenuating Raf-1/MEK1/Sp-1 signaling along with altered eNOS activities. In: American Journal of Pathology. 2013 ; Vol. 183, No. 2. pp. 617-625.
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