IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration

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

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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, ECsmediated 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.

Original languageEnglish (US)
Article numbere13440
JournalPloS one
Volume5
Issue number10
DOIs
StatePublished - Nov 17 2010

Fingerprint

Macrophages
angiogenesis
Infiltration
Reactive Oxygen Species
macrophages
Endothelial cells
Bone
reactive oxygen species
Endothelial Cells
Actins
Bone Marrow Cells
bone marrow
mice
endothelial cells
Muscle
Inflammation
Thioglycolates
Blood
Microfilament Proteins
Muscles

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration. / Urao, Norifumi; Razvi, Masooma; Oshikawa, Jin; McKinney, Ronald D.; Chavda, Rupal; Bahou, Wadie F.; Fukai, Tohru; Ushio-Fukai, Masuko.

In: PloS one, Vol. 5, No. 10, e13440, 17.11.2010.

Research output: Contribution to journalArticle

Urao, Norifumi ; Razvi, Masooma ; Oshikawa, Jin ; McKinney, Ronald D. ; Chavda, Rupal ; Bahou, Wadie F. ; Fukai, Tohru ; Ushio-Fukai, Masuko. / IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration. In: PloS one. 2010 ; Vol. 5, No. 10.
@article{d36a452eab394887b92daf28f1f10d1a,
title = "IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration",
abstract = "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, ECsmediated 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 and Masooma Razvi and Jin Oshikawa and McKinney, {Ronald D.} and Rupal Chavda and Bahou, {Wadie F.} and Tohru Fukai and Masuko Ushio-Fukai",
year = "2010",
month = "11",
day = "17",
doi = "10.1371/journal.pone.0013440",
language = "English (US)",
volume = "5",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - IQGAP1 is involved in post-ischemic neovascularization by regulating angiogenesis and macrophage infiltration

AU - Urao, Norifumi

AU - Razvi, Masooma

AU - Oshikawa, Jin

AU - McKinney, Ronald D.

AU - Chavda, Rupal

AU - Bahou, Wadie F.

AU - Fukai, Tohru

AU - Ushio-Fukai, Masuko

PY - 2010/11/17

Y1 - 2010/11/17

N2 - 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, ECsmediated 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.

AB - 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, ECsmediated 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.

UR - http://www.scopus.com/inward/record.url?scp=78149436950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78149436950&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0013440

DO - 10.1371/journal.pone.0013440

M3 - Article

C2 - 20976168

AN - SCOPUS:78149436950

VL - 5

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 10

M1 - e13440

ER -