Characterization of Endocrine Gland-derived Vascular Endothelial Growth Factor Signaling in Adrenal Cortex Capillary Endothelial Cells

• Published in: The Journal of biological chemistry Vol. 277; no. 10; pp. 8724 - 8729
• Main Authors: Lin, Rui, LeCouter, Jennifer, Kowalski, Joe, Ferrara, Napoleone
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.03.2002; American Society for Biochemistry and Molecular Biology
• Subjects: Adrenal Cortex - blood supply; Adrenal Cortex - metabolism; Animals; Blotting, Western; Cattle; Cell Division; Cell Movement; Cell Survival; Dose-Response Relationship, Drug; Endocrine Glands - metabolism; Endothelial Growth Factors - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Enzyme Activation; Enzyme Inhibitors - pharmacology; Lymphokines - metabolism; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type III; Pertussis Toxin; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Precipitin Tests; Signal Transduction; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Virulence Factors, Bordetella - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110594200

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) has been recently identified as a mitogen specific for the endothelium of steroidogenic glands. Here we report a characterization of the signal transduction of EG-VEGF in a responsive cell type, bovine adrenal cortex-derived endothelial (ACE) cells. EG-VEGF led to a time- and dose-dependent phosphorylation of p44/42 MAPK. This effect was blocked by pretreatment with pertussis toxin, suggesting that Gαi plays an important role in mediating EG-VEGF-induced activation of MAPK signaling. The inhibitor of p44/42 MAPK phosphorylation PD 98059 resulted in suppression of both proliferation and migration in response to EG-VEGF. EG-VEGF also increased the phosphorylation of Akt in a phosphatidylinositol 3-kinase-dependent manner. Consistent with such an effect, EG-VEGF was a potent survival factor for ACE cells. We also identified endothelial nitric-oxide synthase as one of the downstream targets of Akt activation. Phosphorylation of endothelial nitric-oxide synthase in ACE cells was stimulated by EG-VEGF with a time course correlated to the Akt phosphorylation. Our data demonstrate that EG-VEGF, possibly through binding to a G-protein coupled receptor, results in the activation of MAPK p44/42 and phosphatidylinositol 3-kinase signaling pathways, leading to proliferation, migration, and survival of responsive endothelial cells.