H-Ras Regulates Angiogenesis and Vascular Permeability by Activation of Distinct Downstream Effectors
Year: 2008
Type: article
Abstract: Angiogenesis and vascular permeability occur following endothelium activation by vascular endothelial growth factor (VEGF). Downstream mechanisms that define these vascular responses remain unknown. H-Ras activation has been associated with the angiogenic response. However, active H-Ras initiates a wide spectrum of other biological responses through multiple downstream effectors. To identify vascular signaling by H-Ras and the immediate effectors we activated the extracellular signal regulated kinase/mitogen-activated protein kinase or phosphatidylinositol 3-kinase (PI3K) pathways in chicken and mouse endothelial tissues by ectopic expression of the Ras effector mutants H-RasV12S35 or H-RasV12C40, respectively. Constitutive activation of the extracellular signal-regulate kinase/mitogen-activated protein kinase pathway by H-RasV12S35 was sufficient to induce angiogenesis and not vascular permeability, whereas activation of the PI3K pathway by H-RasV12C40 was required for both angiogenesis and vascular permeability. Pharmacological inhibition of PI3K (alpha/beta) suppressed both Ras- or VEGF-mediated vascular response in vivo and survival of primary human endothelial cells in vitro. However, inhibition of PI3K (gamma/delta) suppressed Ras- or VEGF-mediated vascular permeability in vivo, with no effect on survival of primary endothelial cells. This was supported by genetic studies because PI3K p110gamma knockout mice showed impaired vascular permeability response to VEGF or H-RasV12C40 treatment yet produced a wild-type angiogenic response to H-RasV12S35. We conclude that downstream of VEGF, H-Ras serves as a cellular switch that controls neovascularization and vascular permeability by activation of distinct effectors.
Source: Circulation Research
Authors: Doinita Serban, Jie Leng, David Cheresh
Institutions: University of California San Diego, Moores Cancer Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1648785187, G2003983467, Integrin alpha v beta 3 promotes resistance to EGF receptor inhibitors, CRAF-mediated vascular resistance to cancer therapies, Endothelial Barrier Function Regulation by VEGF, VEGF and PDGF in angiogenesis and tumor progression, Combinatorial Chemistry and Cancer Target, Regulation of cell invasion by apoptotic mechanisms, Integrin Signaling in Hemostasis and Blood Diseases
OpenAlex ID: W2120014985