IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration.
IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration.
复制标题
DOI：
10.1371/journal.pone.0013440
复制
发表时间：
2010-10-15
期刊：
影响因子：
3.7
通讯作者：
Ushio-Fukai M
中科院分区：
文献类型：
--
作者：
Urao N;Razvi M;Oshikawa J;McKinney RD;Chavda R;Bahou WF;Fukai T;Ushio-Fukai M
新生血管是缺血性损伤的重要修复机制，它依赖于炎症、血管生成和活性氧（ROS）。IQGAP1是一种肌动蛋白结合支架蛋白，是肌动蛋白细胞骨架和运动的关键调节因子。我们之前证明，IQGAP1介导血管内皮生长因子（VEGF）诱导的ROS产生和培养内皮细胞（ECs）的迁移；然而，其在缺血后新生血管中的作用尚不清楚。左股动脉结扎诱导缺血，导致缺血腿部Mac3+巨噬细胞和CD31+毛细血管样内皮细胞中IQGAP1表达升高。通过激光多普勒血流、毛细血管密度和α-肌动蛋白阳性小动脉评价，缺乏IQGAP1的小鼠缺血后新生血管明显减少。此外，IQGAP1−/−小鼠缺血肌肉中巨噬细胞浸润和ROS生成减少，导致肌肉再生受损，坏死和纤维化增加。这些基因敲除小鼠外周血中骨髓（BM）来源细胞的数量不受影响。骨髓移植显示，IQGAP1在骨髓源性细胞和组织驻留细胞（如内皮细胞）中表达，是缺血后新生血管形成所必需的。此外，在IQGAP1−/−小鼠中，巯基乙酸酯诱导的腹腔巨噬细胞募集和ROS产生被抑制。在体外，IQGAP1−/−bm来源的巨噬细胞显示出迁移和粘附能力的抑制，这可能解释了IQGAP1−/−小鼠中巨噬细胞向缺血组织募集的缺陷。IQGAP1不仅通过调控内皮细胞介导的血管生成，还通过调控巨噬细胞浸润和ROS生成，在缺血后血管形成中发挥关键作用。因此，IQGAP1是炎症和血管生成依赖性缺血性心血管疾病的潜在治疗靶点。
Neovascularization is an important repair mechanism in response to ischemic injury and is dependent on inflammation, angiogenesis and reactive oxygen species (ROS). IQGAP1, an actin-binding scaffold protein, is a key regulator for actin cytoskeleton and motility. We previously demonstrated that IQGAP1 mediates vascular endothelial growth factor (VEGF)-induced ROS production and migration of cultured endothelial cells (ECs); however, its role in post-ischemic neovascularization is unknown. Ischemia was induced by left femoral artery ligation, which resulted in increased IQGAP1 expression in Mac3+ macrophages and CD31+ capillary-like ECs in ischemic legs. Mice lacking IQGAP1 exhibited a significant reduction in the post-ischemic neovascularization as evaluated by laser Doppler blood flow, capillary density and α-actin positive arterioles. Furthermore, IQGAP1−/− mice showed a decrease in macrophage infiltration and ROS production in ischemic muscles, leading to impaired muscle regeneration and increased necrosis and fibrosis. The numbers of bone marrow (BM)-derived cells in the peripheral blood were not affected in these knockout mice. BM transplantation revealed that IQGAP1 expressed in both BM-derived cells and tissue resident cells, such as ECs, is required for post-ischemic neovascularization. Moreover, thioglycollate-induced peritoneal macrophage recruitment and ROS production were inhibited in IQGAP1−/− mice. In vitro, IQGAP1−/− BM-derived macrophages showed inhibition of migration and adhesion capacity, which may explain the defective macrophage recruitment into the ischemic tissue in IQGAP1−/− mice. IQGAP1 plays a key role in post-ischemic neovascularization by regulating, not only, ECs-mediated angiogenesis but also macrophage infiltration as well as ROS production. Thus, IQGAP1 is a potential therapeutic target for inflammation- and angiogenesis-dependent ischemic cardiovascular diseases.
登录
查看更多内容
DIA1和IQGAP1在细胞迁移和吞噬杯形成中相互作用。
影响因子：
7.8
作者：
Brandt, Dominique T.;Marion, Sabrina;Griffiths, Gareth;Watanabe, Takashi;Kaibuchi, Kozo;Grosse, Robert
通讯作者：
Grosse, Robert
DOI：
10.1152/ajplung.00530.2007
发表时间：
2008-10-01
影响因子：
4.9
作者：
Bogatkevich, Galina S.;Ludwicka-Bradley, Anna;Silver, Richard M.
通讯作者：
Silver, Richard M.
影响因子：
4.8
作者：
Le Clainche, Christophe;Schlaepfer, Dominik;Kroschewski, Ruth
通讯作者：
Kroschewski, Ruth
影响因子：
20.3
作者：
Munugalavadla, V;Borneo, J;Kapur, R
通讯作者：
Kapur, R
影响因子：
5.3
作者：
Li, SH;Wang, QJ;Bernards, A
通讯作者：
Bernards, A