Editors' ChoiceCell Biology

Angiopoietin-1 Uncouples the VEGF Receptor from Src

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Science Signaling  22 Jan 2008:
Vol. 1, Issue 3, pp. ec24
DOI: 10.1126/stke.13ec24

Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) play complementary roles in vascular development during embryogenesis. In the adult, VEGF signaling increases vascular permeability and Ang1 blocks this VEGF-mediated response. Gavard et al. provide evidence that this function of Ang1 is mediated by its actions on the endothelial cells, preventing them from responding to VEGF signaling that triggers disruption of adherens junctions. When injected subcutaneously in mice, Ang1 prevented dermal vascular permeability in response to VEGF injection (acute in vivo vascular permeability model). Experiments with cultured mouse endothelial cells revealed that Ang1 did not prevent VEGF from stimulating downstream effectors involved in proliferation (phosphorylation of Akt, extracellular signal-regulated kinases 1 and 2, and focal adhesion kinase) but did prevent disruption of endothelial barrier function by VEGF. Preexposure of endothelial cell cultures to Ang1 inhibited the ability of VEGF to stimulate the phosphorylation on residue Ser665 and subsequent endocytosis of the adhesion molecule VE-cadherin, an event associated with disruption of adherens junctions that connect cells to each other. A similar effect on phosphorylation and endocytosis was observed in the acute in vivo vascular permeability model. In cultured endothelial cells, Ang1 prevented the VEGF-mediated activation of Src but did not affect VEGF-mediated activation of two other Src family members, Fyn and Yes. Ang1 stimulated RhoA activation, and the ability of Ang1 to prevent VEGF-mediated endothelial barrier disruption was lost in cells in which RhoA activity was decreased (by RNA interference techniques, or expression of a dominant-negative mutant, or pharmacological inhibition). A downstream target of RhoA is mDia, and knockdown of either mDia1 or mDia2 prevented Ang1 from inhibiting VEGF-stimulated endothelial permeability, whereas overexpression of a constitutively active form of mDia1 blocked VEGF-mediated endothelial permeability. Ang1 stimulated the association of Src with mDia1 and prevented the accumulation of VEGF receptor-Src complexes in response to VEGF. Thus, by sequestering Src away from the VEGF receptor, Ang1 prevents VEGF-mediated vascular permeability without compromising VEGF-mediated proangiogenic signaling.

J. Gavard, V. Patel. J. S. Gutkind, Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev. Cell 14, 25-36 (2008). [PubMed]

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