PHD2 regulates arteriogenic macrophages through TIE2 signalling.
PHD2 regulates arteriogenic macrophages through TIE2 signalling.
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DOI：
10.1002/emmm.201302695
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发表时间：
2013-06
影响因子：
11.1
通讯作者：
Mazzone, Massimiliano
中科院分区：
文献类型：
--
作者：
Hamm, Alexander;Veschini, Lorenzo;Takeda, Yukiji;Costa, Sandra;Delamarre, Estelle;Squadrito, Mario Leonardo;Henze, Anne-Theres;Wenes, Mathias;Serneels, Jens;Pucci, Ferdinando;Roncal, Carmen;Anisimov, Andrey;Alitalo, Kari;De Palma, Michele;Mazzone, Massimiliano
主动脉路径的闭塞将血流重新导向侧支循环。我们以前报道，巨噬细胞基因修饰表达低水平的脯氨酰羟化酶结构域蛋白2（PHD 2）显示动脉生成表型，促进侧支血管的形成，并保护骨骼肌缺血性坏死。然而，这一过程背后的分子机制是未知的。在这里，我们证明，股动脉闭塞诱导开关巨噬细胞表型通过血管生成素-1（ANG 1）介导的Phd 2抑制。通过可溶性陷阱阻断ANG阻止了巨噬细胞中Phd 2表达的下调及其表型转换，从而抑制了侧枝生长。ANG 1依赖性Phd 2抑制启动了由巨噬细胞中ANG受体TIE 2诱导介导的前馈回路。基因沉默和细胞耗竭策略表明，巨噬细胞中的TIE 2诱导是促进其促动脉生成功能所必需的，从而使动脉阻塞后的侧支血管形成成为可能。这些结果表明TIE 2在维持巨噬细胞原位编程为促动脉生成的M2样表型中起着不可或缺的作用，这表明了治疗缺血性疾病的可能的新途径。
Occlusion of the main arterial route redirects blood flow to the collateral circulation. We previously reported that macrophages genetically modified to express low levels of prolyl hydroxylase domain protein 2 (PHD2) display an arteriogenic phenotype, which promotes the formation of collateral vessels and protects the skeletal muscle from ischaemic necrosis. However, the molecular mechanisms underlying this process are unknown. Here, we demonstrate that femoral artery occlusion induces a switch in macrophage phenotype through angiopoietin-1 (ANG1)-mediated Phd2 repression. ANG blockade by a soluble trap prevented the downregulation of Phd2 expression in macrophages and their phenotypic switch, thus inhibiting collateral growth. ANG1-dependent Phd2 repression initiated a feed-forward loop mediated by the induction of the ANG receptor TIE2 in macrophages. Gene silencing and cell depletion strategies demonstrate that TIE2 induction in macrophages is required to promote their proarteriogenic functions, enabling collateral vessel formation following arterial obstruction. These results indicate an indispensable role for TIE2 in sustaining in situ programming of macrophages to a proarteriogenic, M2-like phenotype, suggesting possible new venues for the treatment of ischaemic disorders.
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影响因子：
37.8
作者：
Anisimov, Andrey;Tvorogov, Denis;Alitalo, Kari
通讯作者：
Alitalo, Kari
影响因子：
20.3
作者：
Fantin, Alessandro;Vieira, Joaquim M.;Ruhrberg, Christiana
通讯作者：
Ruhrberg, Christiana
影响因子：
11.2
作者：
Daly, Christopher;Eichten, Alexandra;Thurston, Gavin
通讯作者：
Thurston, Gavin
影响因子：
50.3
作者：
Mazzieri, Roberta;Pucci, Ferdinando;De Palma, Michele
通讯作者：
De Palma, Michele
影响因子：
11.2
作者：
Coffelt, Seth B.;Tal, Andrea O.;Lewis, Claire E.
通讯作者：
Lewis, Claire E.