Chemokine-coupled β2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis.
Chemokine-coupled β2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis.
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DOI：
10.1084/jem.20132130
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发表时间：
2014-09-22
期刊：
影响因子：
--
通讯作者：
Bender JR
中科院分区：
文献类型：
--
作者：
Morrison AR;Yarovinsky TO;Young BD;Moraes F;Ross TD;Ceneri N;Zhang J;Zhuang ZW;Sinusas AJ;Pardi R;Schwartz MA;Simons M;Bender JR
单核细胞是损伤后动脉生成所必需的，其主要作用之一是产生VEGF;然而，其背后的机制尚未确定。莫里森等人发现趋化因子和整联蛋白刺激之间通过Rac 2的联系，其涉及肌球蛋白重链重新分布RNA稳定蛋白HuR以增加VEGF表达。髓样细胞是动脉生成的重要贡献者，但其关键的分子触发器和细胞效应器在很大程度上是未知的。我们报告，在炎症单核细胞中，趋化因子受体（CCR 2）和粘附受体（β2整合素）结合导致激活的Rac 2和肌球蛋白9（Myh 9）（肌球蛋白IIA的重链）之间的相互作用，导致血管内皮生长因子A（VEGF-A）表达增强和动脉生成诱导。在人单核细胞中，CCL 2刺激与ICAM-1粘附偶联导致RNA结合蛋白HuR的快速核-胞质易位。HuR的这种激活及其VEGF-A mRNA的稳定化是Rac 2依赖性的，Rac 2相互作用物的蛋白质组学分析鉴定了226 kD蛋白Myh 9。诱导的Rac 2-Myh 9相互作用的水平与HuR易位的程度强烈相关。在Myh 9 −/−巨噬细胞中不存在CCL 2偶联的ICAM-1粘附驱动的HuR易位和随后的VEGF-A mRNA稳定。在骨髓特异性Myh 9 −/−小鼠中，巨噬细胞VEGF-A产生、缺血组织VEGF-A水平和后肢缺血血流恢复受损，尽管保留了巨噬细胞向缺血肌肉的募集。微CT动脉造影确定的损害是有缺陷的诱导动脉生成，而发育血管生成不受影响。这些结果将巨噬细胞置于缺血诱导的动脉生成的中心，并且它们确立了肌球蛋白IIA在调节组织中VEGF-A表达的信号转导事件中的新作用。
Monocytes are required for arteriogenesis after injury and one of their major roles is to produce VEGF; however, the mechanisms behind this have not been identified. Morrison et al. find a link between chemokine and integrin stimulation through Rac2 that involves myosin heavy chain to redistribute the RNA stabilizing protein HuR to augment VEGF expression. Myeloid cells are important contributors to arteriogenesis, but their key molecular triggers and cellular effectors are largely unknown. We report, in inflammatory monocytes, that the combination of chemokine receptor (CCR2) and adhesion receptor (β2 integrin) engagement leads to an interaction between activated Rac2 and Myosin 9 (Myh9), the heavy chain of Myosin IIA, resulting in augmented vascular endothelial growth factor A (VEGF-A) expression and induction of arteriogenesis. In human monocytes, CCL2 stimulation coupled to ICAM-1 adhesion led to rapid nuclear-to-cytosolic translocation of the RNA-binding protein HuR. This activation of HuR and its stabilization of VEGF-A mRNA were Rac2-dependent, and proteomic analysis for Rac2 interactors identified the 226 kD protein Myh9. The level of induced Rac2–Myh9 interaction strongly correlated with the degree of HuR translocation. CCL2-coupled ICAM-1 adhesion-driven HuR translocation and consequent VEGF-A mRNA stabilization were absent in Myh9−/− macrophages. Macrophage VEGF-A production, ischemic tissue VEGF-A levels, and flow recovery to hind limb ischemia were impaired in myeloid-specific Myh9−/− mice, despite preserved macrophage recruitment to the ischemic muscle. Micro-CT arteriography determined the impairment to be defective induced arteriogenesis, whereas developmental vasculogenesis was unaffected. These results place the macrophage at the center of ischemia-induced arteriogenesis, and they establish a novel role for Myosin IIA in signal transduction events modulating VEGF-A expression in tissue.
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影响因子：
11.8
作者：
Lanahan, Anthony A.;Hermans, Karlien;Claes, Filip;Kerley-Hamilton, Joanna S.;Zhuang, Zhen W.;Giordano, Frank J.;Carmeliet, Peter;Simons, Michael
通讯作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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56.9
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影响因子：
20.3
作者：
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