HB-EGF promotes angiogenesis in endothelial cells via PI3-kinase and MAPK signaling pathways.
OBJECTIVE
Heparin-binding EGF-like growth factor (HB-EGF) belongs to the epidermal growth factor (EGF) superfamily of ligands. It has been implicated as a regulator of angiogenesis. However, the mechanisms by which HB-EGF promotes angiogenesis are unknown. The goal of the present study was to define the pathways by which HB-EGF stimulates angiogenesis in endothelial cells.


METHODS
To characterize the angiogenic activity of HB-EGF, we treated human umbilical vein endothelial cells (HUVEC) with HB-EGF and analyzed the effects on cell proliferation, migration and tube formation. Side-by-side assays with EGF were used for comparison.


RESULTS
Both HB-EGF and EGF stimulated HUVEC migration in scratch assays and promoted vascular tube formation in 2D-angiogenesis assays, without inducing cell proliferation. HB-EGF- and EGF-induced HUVEC migration and capillary tube formation were dependent upon activation of PI3K, MAPK and eNOS. Importantly, HB-EGF-and EGF-induced tube formation was comparable to, but were independent of tube formation induced by VEGF.


CONCLUSIONS
We have demonstrated that HB-EGF and EGF induce angiogenesis via activation of PI3K, MAPK and eNOS in a VEGF-independent fashion. Thus, the role played by HB-EGF in stimulating physiologic processes such as wound healing in vivo may be dependent, in part, on its ability to promote angiogenesis.
Mehta
Veela B
VB
Department of Pediatric Surgery, The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.
Besner
Gail E
GE
D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases