Macrophage β2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis.
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 marrow-derived 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.
Department of Medicine, Raymond and Beverly Sackler Foundation Cardiovascular Laboratory, Yale University, New Haven, Connecticut 06511, USA.
Jiange
J
Zhang
Yasha
Y
Modi
Timur
T
Yarovinsky
Jun
J
Yu
Mark
M
Collinge
Themis
T
Kyriakides
Yizhun
Y
Zhu
William C
WC
Sessa
Ruggero
R
Pardi
Jeffrey R
JR
Bender
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D055786:Gene Knockout Techniques; D006614:Hindlimb / Q000098:blood supply; D007249:Inflammation / Q000150:complications; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods
D043925:Angiogenesis Inducing Agents; D018821:CD18 Antigens; D051959:ELAV Proteins; D012333:RNA, Messenger