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Insulin‐like growth factor binding protein‐3 induces angiogenesis through IGF‐I‐ and SphK1‐dependent mechanisms
Author(s) -
GRANATA R.,
TROVATO L.,
LUPIA E.,
SALA G.,
SETTANNI F.,
CAMUSSI G.,
GHIDONI R.,
GHIGO E.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02431.x
Subject(s) - angiogenesis , insulin like growth factor , growth factor , medicine , chemistry , insulin , endocrinology , microbiology and biotechnology , cancer research , biology , receptor
Summary. Angiogenesis is critical for development and repair, and is a prominent feature of many pathological conditions. Based on evidence that insulin‐like growth factor binding protein (IGFBP)‐3 enhances cell motility and activates sphingosine kinase (SphK) in human endothelial cells, we have investigated whether IGFBP‐3 plays a role in promoting angiogenesis. IGFBP‐3 potently induced network formation by human endothelial cells on Matrigel. Moreover, it up‐regulated proangiogenic genes, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)‐2 and ‐9. IGFBP‐3 even induced membrane‐type 1 MMP (MT1‐MMP), which regulates MMP‐2 activation. Decreasing SphK1 expression by small interfering RNA (siRNA), blocked IGFBP‐3‐induced network formation and inhibited VEGF, MT1‐MMP but not IGF‐I up‐regulation. IGF‐I activated SphK, leading to sphingosine‐1‐phosphate (S1P) formation. The IGF‐I effect on SphK activity was blocked by specific inhibitors of IGF‐IR, PI3K/Akt and ERK1/2 phosphorylation. The disruption of IGF‐I signaling prevented the IGFBP‐3 effect on tube formation, SphK activity and VEGF release. Blocking ERK1/2 signaling caused the loss of SphK activation and VEGF and IGF‐I up‐regulation. Finally, IGFBP‐3 dose‐dependently stimulated neovessel formation into subcutaneous implants of Matrigel in vivo . Thus, IGFBP‐3 positively regulates angiogenesis through involvement of IGF‐IR signaling and subsequent SphK/S1P activation.