Macrophage β 2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis

Jiange Zhang, Yasha Modi, Timur Yarovinsky, Jun Yu, Mark Collinge, Themis Kyriakides, Yizhun Zhu, William C. Sessa, Ruggero Pardi, Jeffrey R. Bender

Research output: Contribution to journalArticle

Abstract

HuR is a member of the Drosophila Elav protein family that binds mRNA degradation sequences and prevents RNase-mediated degradation. Such HuR-mediated mRNA stabilization, which is stimulated by integrin engagement and is controlled at the level of HuR nuclear export, is critically involved in T-cell cytokine production. However, HuR's role in macrophage soluble factor production, in particular in response to angiogenic stimuli, has not yet been established. We show that the labile transcripts that encode vascular endothelial growth factor and matrix metalloproteinase-9 are stabilized when murine macrophages adhere to the β 2 integrin ligand intercellular adhesion molecule-1. This mRNA stabilization response was absent in bone marrowderived macrophages obtained from conditional macrophage-specific HuR knockout mice. The microvascular angiogenic response to an inflammatory stimulus (ie, subcutaneous polyvinyl alcohol sponge implantation) was markedly diminished in these macrophage HuR knockout mice despite the equal levels of macrophage localization to those observed in littermate wild-type controls. Furthermore, blood flow recovery and ischemic muscle neovascularization after femoral artery ligation were impaired in the conditional macrophage-specific HuR knockout mice. These results demonstrate that dynamic effects on mRNA, mediated by the RNA-binding and RNA-stabilizing protein HuR, are required for macrophage production of angiogenic factors, which play critical roles in the neovascular responses to a variety of stimuli, including tissue ischemia.

Original languageEnglish
Pages (from-to)1751-1760
Number of pages10
JournalAmerican Journal of Pathology
Volume180
Issue number4
DOIs
Publication statusPublished - Apr 2012

    Fingerprint

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Zhang, J., Modi, Y., Yarovinsky, T., Yu, J., Collinge, M., Kyriakides, T., Zhu, Y., Sessa, W. C., Pardi, R., & Bender, J. R. (2012). Macrophage β 2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis. American Journal of Pathology, 180(4), 1751-1760. https://doi.org/10.1016/j.ajpath.2011.12.025