IQGAP1 Is Involved in Post-Ischemic Neovascularization by Regulating Angiogenesis and Macrophage Infiltration.pdf (7.89 MB)
Download file

IQGAP1 Is Involved in Post-Ischemic Neovascularization by Regulating Angiogenesis and Macrophage Infiltration

Download (7.89 MB)
journal contribution
posted on 27.05.2011, 00:00 by Norifumi Urao, Masooma Razvi, Jin Oshikawa, Ronald D. McKinney, Rupal Chavda, Wadie F. Bahou, Tohru Fukai, Masuko Ushio-Fukai
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.

Funding

This research was supported by National Institutes of Health (NIH) R01 Heart and Lung (HL)077524 and HL077524-S1 (to M.U.-F.), HL070187 (to T.F.), American Heart Association (AHA) Grant-In-Aid 0755805Z (to M.U.-F.) and AHA National Center Research Program (NCRP) Innovative Research Grant 0970336N (to M.U.-F), AHA Post-doctoral Fellowship 09POST2250151 (to N.U.), Uehara Memorial Foundation and Naito Foundation (to J.O.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

History

Publisher Statement

© 2010 Urao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The original source for this publication is at Public Library of Science. DOI: 10.1371/journal.pone.0013440

Publisher

Public Library of Science

Language

en_US

issn

1923-6203

Issue date

15/10/2010

Usage metrics

Categories

Exports