Activated Ras induces a proangiogenic phenotype in primary endothelial cells

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Angiogenic factors modify endothelial cell phenotype, promoting new blood vessel formation.
• Ras signaling is crucial for vascular endothelial growth factor (VEGF)-induced angiogenic responses.
• VEGF signaling involves multiple pathways, some independent of Ras activation.

Purpose of the Study:

• To investigate if Ras activation alone is sufficient to induce angiogenic responses in primary endothelial cells.
• To determine the downstream signaling pathways involved in Ras-mediated angiogenesis.
• To assess the role of Ras activation in endothelial cell proliferation and migration.

Main Methods:

• Utilized an activated Ras(V12) mutant in primary endothelial cells.
• Assessed phenotypic changes including membrane ruffling, branching morphogenesis, DNA synthesis, and cell migration.
• Analyzed the involvement of PI3K/AKT, Erk, and Jnk signaling pathways.
• Investigated the effects of inhibiting Erk and PI3K signaling.
• Determined if Ras(V12) effects were mediated by increased VEGF secretion.

Main Results:

• Activated Ras(V12) induced significant membrane ruffling, branching morphogenesis, DNA synthesis, and cell migration.
• Ras(V12) upregulated PI3K/AKT, Erk, and Jnk signaling pathways.
• Erk inhibition partially reduced migration and blocked proliferation; PI3K inhibition modestly reduced migration but did not affect DNA synthesis.
• Jnk signaling was critical for both proliferation and migration.
• Ras(V12) effects were independent of increased autocrine VEGF secretion.

Conclusions:

• Ras activation is sufficient to induce a pro-angiogenic phenotype in primary endothelial cells.
• Specific signaling pathways (Erk, PI3K, Jnk) are differentially regulated by Ras in promoting angiogenic responses.
• Activating Ras mutations may be sufficient to drive angiogenesis and the development of vascular anomalies.