Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 88, Issue 2, Pages 900-907Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2002-020472
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Funding
- NCI NIH HHS [1UO1-CA-84128, U01 CA084128] Funding Source: Medline
- NIAID NIH HHS [1R01-AI-40203] Funding Source: Medline
- NIA NIH HHS [1R01-AG-20954, R01 AG020954] Funding Source: Medline
- NICHD NIH HHS [K12 HD034610, 5P30-HD-34610] Funding Source: Medline
- NIDDK NIH HHS [F32 DK009985-02, T32 DK007688, R01 DK047591, F32 DK009985, 2R01-DK-47591, 5T32-DK-007688, K08-DK-02876, K08 DK002876] Funding Source: Medline
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Angiogenic factors, such as vascular endothelial-derived growth factor (VEGF) and IGF-I, play pivotal roles in endothelial proliferation and migration. IGF binding protein-3 (IGFBP-3) is emerging as a key regulator of cell growth and apoptosis, both as an IGF antagonist and as an independent molecule. We investigated the role of IGFBP-3 in VEGF-mediated survival of human macrovascular umbilical vein endothelial cells (HUVEC). Specific commercial ELISAs quantified cell proliferation and apoptosis, and Akt phosphorylation was assessed by immunoblots and confocal microscopy. IGF-I and VEGF significantly stimulated HUVEC proliferation and survival. Addition of IGFBP-3 reversed both IGF- and VEGF-induced proliferation and prevented the survival induced by these factors. The antiproliferative and proapoptotic effects of exogenous IGFBP-3 upon VEGF-induced HUVEC survival were not inhibited by blockade of the type 1 IGF receptor with alphaIR-3 immunoglobulin, which fully prevented IGF actions. An IGFBP-3 mutant, which binds IGFs normally but has a substituted mid-region domain, lost the ability to inhibit VEGF actions. VEGF-induced phosphorylation of Akt, as evident by both specific immunoblots and confocal microscopy, was significantly and rapidly reduced in the presence of IGFBP-3, as well as wortmannin.
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