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See detailNew prospects in the roles of the C-terminal domains of VEGF-A and their cooperation for ligand binding, cellular signaling and vessels formation.
Delcombel, Romain ULg; Janssen, Lauriane ULg; Vassy, Roger et al

in Angiogenesis (2013), 16(2), 353-71

VEGF-A is a crucial growth factor for blood vessel homeostasis and pathological angiogenesis. Due to alternative splicing of its pre-mRNA, VEGF-A is produced under several isoforms characterized by the ... [more ▼]

VEGF-A is a crucial growth factor for blood vessel homeostasis and pathological angiogenesis. Due to alternative splicing of its pre-mRNA, VEGF-A is produced under several isoforms characterized by the combination of their C-terminal domains, which determines their respective structure, availability and affinity for co-receptors. As controversies still exist about the specific roles of these exon-encoded domains, we systematically compared the properties of eight natural and artificial variants containing the domains encoded by exons 1-4 and various combinations of the domains encoded by exons 5, 7 and 8a or 8b. All the variants (VEGF(111)a, VEGF(111)b, VEGF(121)a, VEGF(121)b, VEGF(155)a, VEGF(155)b, VEGF(165)a, VEGF(165)b) have a similar affinity for VEGF-R2, as determined by Surface plasmon resonance analyses. They strongly differ however in terms of binding to neuropilin-1 and heparin/heparan sulfate proteoglycans. Data indicate that the 6 amino acids encoded by exon 8a must be present and cooperate with those of exons 5 or 7 for efficient binding, which was confirmed in cell culture models. We further showed that VEGF(165)b has inhibitory effects in vitro, as previously reported, but that the shortest VEGF variant possessing also the 6 amino acids encoded by exon 8b (VEGF(111)b) is remarkably proangiogenic, demonstrating the critical importance of domain interactions for defining the VEGF properties. The number, size and localization of newly formed blood vessels in a model of tumour angiogenesis strongly depend also on the C-terminal domain composition, suggesting that association of several VEGF isoforms may be more efficient for treating ischemic diseases than the use of any single variant. [less ▲]

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See detailIsoform 111 of vascular endothelial growth factor (VEGF111) improves angiogenesis of ovarian tissue xenotransplantation
Labied, Soraya ULg; Delforge, Yves ULg; Munaut, Carine ULg et al

in Transplantation (2013), 95(3), 426-433

Background: Cryopreservation of cortex ovarian tissue before anti-cancer therapy is a promising technique for fertility preservation mainly in children and young women. Ischemia in the early stage after ... [more ▼]

Background: Cryopreservation of cortex ovarian tissue before anti-cancer therapy is a promising technique for fertility preservation mainly in children and young women. Ischemia in the early stage after ovarian graft causes massive follicle loss by apoptosis. VEGF111 is a recently described VEGF isoform that does not bind to the extracellular matrix, diffuse extensively and is resistant to proteolysis. These properties confer a significantly higher angiogenic potential to VEGF111 in comparison to the other VEGF isoforms. Methods: We evaluated the morphology of cryopreserved sheep ovarian cortex, grafted in the presence or absence of VEGF111. Ovarian cortex biopsies were embedded in type I collagen with or without VEGF111 addition before transplantation to SCID mice ovaries. Transplants were retrieved 3 days or 3 weeks later. Follicular density, vasculature network, haemoglobin content and cell proliferation were analysed. Results: Addition of VEGF111 increased density of functional capillaries (p=0.01) 3 days after grafting. By double immunostaining of Ki-67 and von Willebrand Factor (vWF) we demonstrated that proliferating endothelial cells were found in 83% of the VEGF111 group when compared to 33% in the control group (p=0.001). This angio-stimulation was associated with a significant enhancement of haemoglobin content (p=0.03). Three weeks after transplantation, the number of primary follicles was significantly higher in VEGF111 grafts (p=0.02). Conclusion: VEGF111 accelerates blood vessels recruitment, functional angiogenesis and improves the viability of ovarian cortex by limiting ischemia and ovarian cortex damage. [less ▲]

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See detailEvaluation of the use of VEGF111 for the treatment of tendon lesions.
Janssen, Lauriane ULg; Kaux, Jean-François ULg; Drion, Pierre ULg et al

Poster (2011, May 20)

Alterations of tendons are common pathologies resulting from repetitive or abnormal mechanical sollicitations. Very frequently lesions become chronic and may even lead to rupture. As there is no current ... [more ▼]

Alterations of tendons are common pathologies resulting from repetitive or abnormal mechanical sollicitations. Very frequently lesions become chronic and may even lead to rupture. As there is no current efficient treatment for curing this type of diseases, new therapeutic approaches are being tested and developed. Injection of platelet-rich plasma (PRP) seems to be a promising treatment by local release of growth factors. Among these factors, VEGF-A is known to induce positive effects on vascular functions and angiogenesis, and could be implicated in the healing process of tendons. Several isoforms of VEGF-A have been described in literature, including VEGF165 and 121. VEGF111 is encoded by exons 1-4 and 8a. The lack of exon 5 enables VEGF111 to resist to proteolytic degradation and the absence of exons 6 and 7 reduces its affinity for several macromolecules present on the cell surface and in the extracellular matrix. In vivo, it has been shown to be highly proangiogenic and diffusible. A 5mm defect was surgically performed in the Achilles tendon of 60 rats. Two hours after closure of the fascia and the skin, an injection within the wound was performed with PBS alone (n=30) or with PBS containing 100 ng of VEGF111 (n=30). 10 rats of each group were sacrificed at days 5, 15 and 30. The operated tendon was then carefully removed and collected for either immunohistochemical analyses or mechanical testing. At each time point, the section and the overall appearance of the repairing tendons were similar for PBS and VEGF111-injected tendon. As compared to controls, injection of VEGF111 seemed to promote a faster angiogenesis, although the number of samples was at this stage too low for performing reliable statistical analysis. Mechanical resistance to rupture of the repairing tendons was also measured. No difference between the two groups was observed after 5 or 15 days. By contrast, increased tensile strength was clearly evidenced in the VEGF-treated group after 30 days. These preliminary data seem to indicate a positive effect of a single VEGF111 injection for restoring the mechanical properties of tendons after their section. Additional experiments are planned for confirmation purposes and for further characterizing the model. It includes a “dose- response” analysis, the use of VEGF165 as an additional control and a study evaluating the effect of several injections. [less ▲]

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