Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability

Anna Eriksson, Renhai Cao, Joy Roy, Katerina Tritsaris, Claes R Wahlestedt, Steen Dissing, Johan Thyberg, Yihai Cao

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Background - Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) induces both angiogenesis and vascular permeability. Although its angiogenic activity has been well characterized, the signaling pathways of VEGF-induced permeability remain poorly understood. Methods and Results - Using the mouse corneal micropocket assay, Miles assay, and a combination of cytochemical, electron microscopic, and biochemical assays, we demonstrate that VEGF-induced vascular leakage partly can be separated from its angiogenic activity. VEGF but not FGF-2 induced capillaries with a highly fenestrated endothelium, a feature linked with increased vascular permeability. A cell-permeable Rac antagonist (TAT-RacN17) converted VEGF-induced, leaky vascular plexuses into well-defined vascular networks. In addition, this Rac mutant blocked formation of VEGF-induced endothelial fenestrations and vascular permeability but only partially inhibited angiogenesis. Studies on endothelial cell cultures further revealed that VEGF stimulated phosphorylation of VEGF receptor-2 (VEGFR-2), leading to activation of Rac as well as increased phosphorylation of phospholipase CT (PLCT), protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), and extracellular regulated kinase (Erk1/2). We further found that phosphatidylinositol-3-OH kinase (PI3K) acted upstream of Rac and Akt-eNOS in VEGF/VEGFR-2 signaling. Conclusions - Our findings indicate that the small GTP-binding protein Rac is a key component in mediation of VEGF-induced vascular permeability but less so in neovascularization. This may have conceptual implications for applying Rac antagonists in treatment and prevention of VEGF-induced vascular leakage and edema in connection with ischemic disorders.

Original languageEnglish
Pages (from-to)1532-1538
Number of pages7
JournalCirculation
Volume107
Issue number11
DOIs
StatePublished - Mar 25 2003
Externally publishedYes

Fingerprint

rac GTP-Binding Proteins
Capillary Permeability
Vascular Endothelial Growth Factor A
Blood Vessels
Vascular Endothelial Growth Factor Receptor
Nitric Oxide Synthase Type III
Phosphorylation
Proto-Oncogene Proteins c-akt
Phospholipases
Fibroblast Growth Factor 2
Phosphatidylinositol 3-Kinases
Endothelium

Keywords

  • Endothelium
  • Ischemia
  • Proteins
  • Receptors
  • Vasculature

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. / Eriksson, Anna; Cao, Renhai; Roy, Joy; Tritsaris, Katerina; Wahlestedt, Claes R; Dissing, Steen; Thyberg, Johan; Cao, Yihai.

In: Circulation, Vol. 107, No. 11, 25.03.2003, p. 1532-1538.

Research output: Contribution to journalArticle

Eriksson, Anna ; Cao, Renhai ; Roy, Joy ; Tritsaris, Katerina ; Wahlestedt, Claes R ; Dissing, Steen ; Thyberg, Johan ; Cao, Yihai. / Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability. In: Circulation. 2003 ; Vol. 107, No. 11. pp. 1532-1538.
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AU - Wahlestedt, Claes R

AU - Dissing, Steen

AU - Thyberg, Johan

AU - Cao, Yihai

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