Synergistic effect of hyaluronan oligosaccharides and vascular endothelial growth factor on angiogenesis in vitro.

2.50
Hdl Handle:
http://hdl.handle.net/10541/95997
Title:
Synergistic effect of hyaluronan oligosaccharides and vascular endothelial growth factor on angiogenesis in vitro.
Authors:
Montesano, R; Kumar, Shant; Orci, L; Pepper, M S
Abstract:
The aim of the present study was to determine whether hyaluronan (HA) degradation products, which have been shown to be angiogenic in vivo, influence endothelial cell invasion of a 3-dimensional matrix, an essential component of the neovascularization process. Using a previously described in vitro assay, we demonstrate that like the angiogenic cytokines basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), HA oligosaccharides (OHA) induce bovine microvascular endothelial cells to invade a 3-dimensional collagen gel within which they form capillary-like tubes, with an optimal effect at approximately 0.5 to 2 micrograms/ml. Strikingly, co-addition of OHA (0.5 - 2 micrograms/ml) and VEGF (30 ng/ml), but not co-addition of OHA and bFGF (10 ng/ml), induced an in vitro angiogenic response that was greater than the sum of the effects elicited by either agent separately. In contrast to OHA, native high molecular weight HA was consistently inactive, whether added alone or in combination with VEGF or bFGF. Because endothelial cell invasion is believed to require extracellular proteolytic activity, we also investigated the effect of OHA on the plasminogen activator (PA)-plasmin system. OHA (0.01 to 1 microgram/ml) but not native high molecular weight HA induced a dose-dependent increase in mRNA levels of urokinase type PA (uPA), urokinase type PA receptor and PA inhibitor type 1, and a parallel increase in the functional activity of urokinase type PA and PA inhibitor type 1, as determined by zymography and reverse zymography, respectively. The effects of OHA on proteolytic activity were additive with those of VEGF, but not with those of bFGF. Taken together, these results demonstrate that OHA modulate the invasive and proteolytic properties of bovine microvascular endothelial cells and synergize specifically with VEGF in the induction of angiogenesis in vitro. We suggest that the synergism between OHA and VEGF plays a role in the regulation of angiogenesis and that it may be exploited therapeutically in situations that would benefit from stimulation of new blood vessel growth.
Affiliation:
Department of Morphology, University Medical Center, Geneva, Switzerland.
Citation:
Synergistic effect of hyaluronan oligosaccharides and vascular endothelial growth factor on angiogenesis in vitro. 1996, 75 (2):249-62 Lab. Invest.
Journal:
Laboratory Investigation
Issue Date:
Aug-1996
URI:
http://hdl.handle.net/10541/95997
PubMed ID:
8765325
Type:
Article
Language:
en
ISSN:
0023-6837
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorMontesano, Ren
dc.contributor.authorKumar, Shanten
dc.contributor.authorOrci, Len
dc.contributor.authorPepper, M Sen
dc.date.accessioned2010-04-08T11:59:40Z-
dc.date.available2010-04-08T11:59:40Z-
dc.date.issued1996-08-
dc.identifier.citationSynergistic effect of hyaluronan oligosaccharides and vascular endothelial growth factor on angiogenesis in vitro. 1996, 75 (2):249-62 Lab. Invest.en
dc.identifier.issn0023-6837-
dc.identifier.pmid8765325-
dc.identifier.urihttp://hdl.handle.net/10541/95997-
dc.description.abstractThe aim of the present study was to determine whether hyaluronan (HA) degradation products, which have been shown to be angiogenic in vivo, influence endothelial cell invasion of a 3-dimensional matrix, an essential component of the neovascularization process. Using a previously described in vitro assay, we demonstrate that like the angiogenic cytokines basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), HA oligosaccharides (OHA) induce bovine microvascular endothelial cells to invade a 3-dimensional collagen gel within which they form capillary-like tubes, with an optimal effect at approximately 0.5 to 2 micrograms/ml. Strikingly, co-addition of OHA (0.5 - 2 micrograms/ml) and VEGF (30 ng/ml), but not co-addition of OHA and bFGF (10 ng/ml), induced an in vitro angiogenic response that was greater than the sum of the effects elicited by either agent separately. In contrast to OHA, native high molecular weight HA was consistently inactive, whether added alone or in combination with VEGF or bFGF. Because endothelial cell invasion is believed to require extracellular proteolytic activity, we also investigated the effect of OHA on the plasminogen activator (PA)-plasmin system. OHA (0.01 to 1 microgram/ml) but not native high molecular weight HA induced a dose-dependent increase in mRNA levels of urokinase type PA (uPA), urokinase type PA receptor and PA inhibitor type 1, and a parallel increase in the functional activity of urokinase type PA and PA inhibitor type 1, as determined by zymography and reverse zymography, respectively. The effects of OHA on proteolytic activity were additive with those of VEGF, but not with those of bFGF. Taken together, these results demonstrate that OHA modulate the invasive and proteolytic properties of bovine microvascular endothelial cells and synergize specifically with VEGF in the induction of angiogenesis in vitro. We suggest that the synergism between OHA and VEGF plays a role in the regulation of angiogenesis and that it may be exploited therapeutically in situations that would benefit from stimulation of new blood vessel growth.en
dc.language.isoenen
dc.subject.meshAdrenal Cortex-
dc.subject.meshAnimals-
dc.subject.meshCattle-
dc.subject.meshCell Line-
dc.subject.meshCells, Cultured-
dc.subject.meshCollagen-
dc.subject.meshDrug Synergism-
dc.subject.meshEndothelial Growth Factors-
dc.subject.meshEndothelium, Vascular-
dc.subject.meshGels-
dc.subject.meshHyaluronic Acid-
dc.subject.meshLymphokines-
dc.subject.meshNeovascularization, Physiologic-
dc.subject.meshOligosaccharides-
dc.subject.meshPlasminogen Activators-
dc.subject.meshVascular Endothelial Growth Factor A-
dc.subject.meshVascular Endothelial Growth Factors-
dc.titleSynergistic effect of hyaluronan oligosaccharides and vascular endothelial growth factor on angiogenesis in vitro.en
dc.typeArticleen
dc.contributor.departmentDepartment of Morphology, University Medical Center, Geneva, Switzerland.en
dc.identifier.journalLaboratory Investigationen
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