TY - JOUR
T1 - Macrophage β 2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis
AU - Zhang, Jiange
AU - Modi, Yasha
AU - Yarovinsky, Timur
AU - Yu, Jun
AU - Collinge, Mark
AU - Kyriakides, Themis
AU - Zhu, Yizhun
AU - Sessa, William C.
AU - Pardi, Ruggero
AU - Bender, Jeffrey R.
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2011.12.025
DO - 10.1016/j.ajpath.2011.12.025
M3 - Article
C2 - 22322302
AN - SCOPUS:84859055291
VL - 180
SP - 1751
EP - 1760
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 4
ER -