IQGAP1 Is Involved in Post-Ischemic Neovascularization by Regulating Angiogenesis and Macrophage InfiltrationReport as inadecuate




IQGAP1 Is Involved in Post-Ischemic Neovascularization by Regulating Angiogenesis and Macrophage Infiltration - Download this document for free, or read online. Document in PDF available to download.

Background

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.

Methodology-Principal Findings

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.

Conclusions-Significance

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.



Author: Norifumi Urao, Masooma Razvi, Jin Oshikawa, Ronald D. McKinney, Rupal Chavda, Wadie F. Bahou, Tohru Fukai, Masuko Ushio-Fukai

Source: http://plos.srce.hr/



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