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See detailRepetitive intrathecal VEGF165 treatment has limited therapeutic effects after spinal cord injury in the rat.
van Neerven, Sabien; Joosten, Elbert A.J.; Brook, Gary A. et al

in Journal of Neurotrauma (2010), 27

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See detailLe VEGF-111 comme nouvel outil thérapeutique des lésions tendineuses
Kaux, Jean-François ULg; Drion, Pierre ULg; Libertiaux, Vincent ULg et al

in 3ème Congrès Commun SFMS - SFTS (2010, September 30)

Introduction : Les lésions tendineuses sont très fréquentes en traumatologie du sport et deviennent fréquemment chroniques. Pour ces raisons, de nouvelles thérapeutiques sont en cours de développement ... [more ▼]

Introduction : Les lésions tendineuses sont très fréquentes en traumatologie du sport et deviennent fréquemment chroniques. Pour ces raisons, de nouvelles thérapeutiques sont en cours de développement. Les injections de concentrés plaquettaires (platelet-rich plasma ou PRP) semblent constituer en ce sens une voie encourageante. Elles agissent par libération locale de divers facteurs de croissance parmi lesquels le VEGF-A (vascular endothelial growth factor-A), connu pour induire un effet positif sur la fonction vasculaire et l’angiogenèse, serait impliqué dans le processus cicatriciel des tendons. Récemment, une nouvelle isoforme du VEGF-A a été identifié : le VEGF-111. Celui-ci est une isoforme biologiquement active du VEGF-A, résistant à la protéolyse et aussi connu pour présenter un effet bénéfique sur les pathologies ischémiques. Pour ces raisons, nous avons pensé que le VEGF-111 pourrait avoir un intérêt thérapeutique pour les pathologies tendineuses. Matériel et méthode : 60 rats de souche Sprague-Dawley adultes ont été séparés en 2 groupes (A: groupe contrôle sans traitement et B: groupe traité par une injection de VEGF-111). Chez ces rats, un défaut de 5mm dans le tendon d’Achille a été réalisé après résection du tendon du plantaire grêle. Les 30 rats du groupe B ont alors bénéficié d’une injection in loco de 100ng de VEGF-111. Les rats ont été euthanasiés par groupe de 20 (10 du groupe A et 10 du groupe B) respectivement à J5, J15 et J30 et le tendon d’Achille en cours de régénération a été disséqué et prélevé. Une étude biomécanique de traction jusqu’à rupture a été réalisée à l’aide de mors type « cryo-jaw ». Résultats : L’analyse de nos résultats montre que la force nécessaire pour rompre le tendon lors du test de traction, était plus importante pour les tendons du groupe B. Ces résultats peuvent être observés dès le 5ème jour. Le rapport entre la force et la masse corporelle du rat augmente dans les 2 groupes avec le temps, mais cette augmentation est plus importante pour les tendons du groupe B. La surface de section du tendon de groupe B s’accroit plus rapidement entre les jours 5 et 15 et ensuite se stabilise. Après 30 jours, les sections tendineuses sont similaires dans les 2 groupes. Enfin, dans le groupe B, les contraintes nécessaires pour obtenir la rupture du tendon, en tenant compte de l’accroissement de sa section, sont similaires entre les jours 5 et 15 et augmentent après un mois. Conclusion : Cette expérience a démontré qu’une injection de 100ng de VEGF-111 stimulait le processus de cicatrisation tendineuse en augmentant la résistance du tendon et les contraintes nécessaires pour rompre celui-ci. D’autres expérimentations avec différentes concentrations de VEGF-111 sont actuellement en cours. [less ▲]

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See detailVEGF-111 as a new therapeutic tool for tendon lesion
Kaux, Jean-François ULg; Drion, Pierre ULg; Libertiaux, Vincent ULg et al

in Osteoarthritis and Cartilage (2010, September), 18(Supplement 2), 22

Introduction: Tendon lesion is one of the most frequent pathology in sports and by physical workers. This pathology often becomes chronic. For this reason, it is of interest to develop new treatments ... [more ▼]

Introduction: Tendon lesion is one of the most frequent pathology in sports and by physical workers. This pathology often becomes chronic. For this reason, it is of interest to develop new treatments. Injection of platelet-rich plasma (PRP) seems to be a promising one by releasing growth factors (GF) locally. Among all the GF released by activated platelets, the vascular endothelial growth factor-A (VEGF-A) is known to induce positive effects on vascular function and angiogenesis, and could be implicated in the healing process of tendons. Recently, a novel VEGF-A isoform was identified, the VEGF-111, a biologically active and proteolysis-resistant VEGF-A isoform, also known to present beneficial effects on ischemic diseases. This prompted us to evaluate whether VEFF-111 would have a therapeutic interest within the framework of the tendon pathology. Methods: 60 Rats were divided into 2 groups: A: control (no injection), B: VEGF-111 treatment. A 5mm defect was surgically induced in rat Achilles tendon after resection of plantaris tendon. Rats received a local injection of VEGF-111 (100ng) in situ after the surgery and were placed in their cages without immobilization. After 5, 15 and 30 days, the traumatized Achilles tendons of 10 rats of both groups were removed and dissected during their healing process. Immediately after sampling, tendons were submitted to a biomechanical tensile test up to rupture, using a “Cryo-jaw”. Rats were then euthanized. Statistical analyses were made with an ANOVA. Values are significant when p-value is below 0.05. Results: Our results shown that the developed force necessary to induce tendon rupture during biomechanical tensile test was greater for tendons which had received an injection of 100ng of VEGF-111. These results were already noticed from day 5 onwards. The ratio between force and weight increased with time in both groups, but this ratio was greater for tendons which had been submitted to an injection of VEGF111. The surface area of the section of the tendons increased between 5 and 15 days followed by a stabilization. After 30 days, sections in both groups were similar. Thus, the constraint was similar after 5 and 15 days but was better for VEGF111 group after one month. Discussion - Conclusion: This experimentation has shown that a 100ng injection of VEGF-111 stimulated tendon healing process as suggested by the increased force needed to break tendons during its healing process and the increased of constraint in comparison with the control group. Other experimentations with different concentration of VEGF111 are now in process. Acknowledgement This experimentation was partially financed by “Standard de Liège 2007” and “Lejeune-Lechien 2008” grants. [less ▲]

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See detailNew use of VEGF in therapeutics: application in tendon lesions
Kaux, Jean-François ULg; Le Goff, Caroline ULg; Drion, Pierre ULg et al

in Clinical Chemistry (2010, July), 56(S6), 111

Introduction: As demonstrated in previous studies, mechanical overload, injury and inflammation, hypoxic condition or any combination of the above could lead to increased expression of VEGF in the tendon ... [more ▼]

Introduction: As demonstrated in previous studies, mechanical overload, injury and inflammation, hypoxic condition or any combination of the above could lead to increased expression of VEGF in the tendon. Thus, VEGF could participate in the healing of pathological tendons. Indeed, some authors are convinced that this neovascularization is the sign of a chronic tendinopathy while others plead in favour of it being a sign of healing processes. The VEGF111, which is a biologically active and proteolysis-resistant VEGF-A isoform, was recently identified. It is induced by ultraviolet B and genotoxic drugs. Experimentation shows that, in nude mice, tumors formed by HEK293 cells expressing VEGF111 develop a more widespread peritumoral neovascularisation than those expressing other VEGF isoforms. Good angiogenic activity and resistance to proteolysis makes VEGF111 a potential beneficial therapeutic option for ischemic diseases. The aim of our study was to determine whether if VEGF111 could have a therapeutic interest in the framework of tendinous pathology. Methods (*): A 5mm defect was surgically induced in Achilles tendon of 60 rats. Rats were divided into 2 groups of 30: A: a control group (no injection) and B: with a VEGF111 injection. The rats of group B received an injection of 100 ng of VEGF111 in situ 1 hour after surgery on the site of the tendon lesion. Afterwards, rats of both groups were placed in their cages without immobilization. After 5, 15 and 30 days, 10 rats of each group were euthanized. The traumatized Achilles tendon of each rat was dissected and removed. Immediately after sampling, tendons were submitted to a biomechanical tensile test up to rupture, using a tensile machine with “Cryo-jaw”. Statistical analyses were made with an ANOVA. Results: A significant increase over time of the force necessary to induce tendon rupture was observed for tendons which had been submitted to an injection of VEGF111 (p=0.016). The force required to break the tendon is always greater for the VEGF111 group (p<0.05). Discussion: We demonstrated that the force necessary to induce the rupture of a rat’s Achilles tendon during biomechanical tensile testing was greater for tendons which had been submitted to an injection of VEGF111. Thus, this experimentation showed that VEGF111 injections could accelerate the tendon healing process and increase the force needed to break tendons in their healing process. Conclusion: VEGF111 could be a new therapy for tendon lesions. However, other experimentation using a rat model with different concentrations of VEGF111 should be made to ascertain the best concentration for this healing process. Acknowledgement: This experimentation was partially financed by “Standard de Liège” and “Lejeune-Lechien” grants. (*) All experimental procedures and protocols used in this investigation were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Liège. [less ▲]

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See detailComparison between platelet-rich plasma (PRP) and vascular endothelial growth factor-111 (VEGF-111) as a therapeutic tool in tendon healing process
Kaux, Jean-François ULg; Drion, Pierre ULg; Libertiaux, Vincent ULg et al

Poster (2010, March 20)

Introduction In spite of the availability of various treatments for tendinopathy, this pathology often becomes chronic. For this reason, it is of interest to develop new treatments. Among them, the ... [more ▼]

Introduction In spite of the availability of various treatments for tendinopathy, this pathology often becomes chronic. For this reason, it is of interest to develop new treatments. Among them, the injection of platelet-rich plasma (PRP) seems to be a promising one. Indeed, several animal models have demonstrated that injection of blood platelets can initiate and stimulate tendon and ligament repair by releasing growth factors (GF) locally. Among all the GF released by activated platelets, the vascular endothelial growth factor-A (VEGF-A) is known to induce positive effects on vascular function and angiogenesis, and could be implicated in the healing process of tendons. Recently, a novel VEGF-A isoform was identified, the VEGF-111, a biologically active and proteolysis-resistant VEGF-A isoform, also known to present beneficial effects on ischemic diseases. This prompted us to evaluate whether VEFF-111 would have a therapeutic interest within the framework of the tendon pathology. Aim of the study: We hypothesized that the healing of ruptured Achilles tendons, which is the last stage of the Blazina’s classification, could be improved by injection of VEGF-111 that was compared to the potential effect of PRP injections using a rat model. Methods: A 5mm defect was surgically induced in rat Achilles tendon after resection of plantaris tendon. Rats were divided into 3 groups: A: control (no injection), B: PRP treatment and C: VEGF-111 treatment. Rats received a local injection of PRP (50µL) or VEGF-111 (100ng) in situ after the surgery and were placed in their cage without immobilization. After 5, 15 and 30 days, the rats were euthanized in each group. The traumatized Achilles tendon of each rat was removed and dissected during the healing process. Immediately after sampling, tendons were submitted to a biomechanical tensile test up to rupture, using a “Cryo-jaw”. Results: Our results show that developed force necessary to induce tendon rupture during biomechanical tensile test was more important for tendons which had received an injection of PRP or VEGF-111. Moreover, the tensile force necessary to break tendons is higher with PRP than with VEGF-111. These results were already noticed from day 5 onwards. Conclusion: This experimentation has shown that both PRP and VEGF-111 injections stimulated tendon healing process as suggested by the increased force needed to break tendons during its healing process. Furthermore, this acceleration of the cicatrisation process was more significant with PRP than with VEGF-111. This could be explained by the release from platelets of a “cocktail” of growth factors acting in synergy on the healing process. Acknowledgement This experimentation was partially financed by “Standard de Liège 2007” and “Lejeune-Lechien 2008” grants. [less ▲]

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See detailAlternative splicing: a promising target for pharmaceutical inhibition of pathological angiogenesis?
Munaut, Carine ULg; Colige, Alain ULg; Lambert, Charles ULg

in Current Pharmaceutical Design (2010), 16(35), 3864-76

In eukaryotes, genes consist in coding sequences (exons) interspersed with non-coding ones (introns). The regulation of alternative inclusion/exclusion of exons, or part of exons, during the maturation of ... [more ▼]

In eukaryotes, genes consist in coding sequences (exons) interspersed with non-coding ones (introns). The regulation of alternative inclusion/exclusion of exons, or part of exons, during the maturation of the pre-mRNA into mRNA (alternative splicing) allows a dramatic increase of the protein versus the gene repertoire. In a number of cases, alternative splicing decision generates proteins with distinct, sometimes opposite, functions from a given gene. Angiogenesis is the process of vascularisation in physiological conditions and a series of pathologies, including cancer where it favours tumour progression and dissemination of metastasis. In this issue, we discuss some key examples showing how alternative splicing may induce a switch from anti-angiogenic to pro-angiogenic functions and reciprocally. For some of these splicing events, the molecular mechanisms that trigger alternative splicing toward one or the other direction start to be elucidated. The emergence of strategies enabling to regulate alternative splicing opens new routes for anti-angiogenic therapies. [less ▲]

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See detailHistological and transcriptional study of angiogenesis and lymphangiogenesis in uninvolved skin, acute pinpoint lesions and established psoriasis plaques: an approach of vascular development chronology in psoriasis
Henno, Audrey ULg; Blacher, Silvia ULg; Lambert, Charles ULg et al

in Journal of Dermatological Science (2010), 57(3), 162-169

Background Dysregulation of angiogenesis and lymphangiogenesis could participate in psoriasis pathogenesis. Analysis of nascent psoriasis lesions should help at identifying early vascular anomalies ... [more ▼]

Background Dysregulation of angiogenesis and lymphangiogenesis could participate in psoriasis pathogenesis. Analysis of nascent psoriasis lesions should help at identifying early vascular anomalies. Objective To analyse vascular development, angiogenesis and lymphangiogenesis markers expression in uninvolved skin in psoriatic patients (N), early psoriasis lesions or pinpoints (PP) and psoriasis plaques (PSO). Methods Skin biopsies were taken in 17 patients in N and in PSO and/or PP. The mRNA steady-state level of angiogenesis and lymphangiogenesis markers was measured by RT-PCR. Immunohistochemistry was performed for von Willebrand factor, podoplanin, Ki-67 and VEGFR3. Blood (BV) and lymphatic (LV) vessels expansion was measured by computer-assisted morphometry. Results Clinical and epidermal aspects indicated that PP are intermediate between N and PSO. While total BV area was already increased in PP similarly to PSO as compared to N, LV area in PP was intermediate between N and PSO. Mean LV size was identical in N and PP and increased in PSO, mean BV size in PP being intermediate between N and PSO. VEGF-A 189 variant was increased in PP as compared to N and PSO. As compared to N, angiogenesis markers (VEGF-A isoforms, PlGF, VEGFR2, NRP-1), VEGF-C and NRP-2 were similarly increased in PP and PSO. Keratin 16 and the lymphangiogenesis markers (VEGFR3, prox-1) were intermediate in PP. Conclusion These data suggest that the expansion of lymphatic vessels occurs after blood vascular development in psoriasis. Expansion of BV in PP could be followed by vessel enlargement during progression to PSO, in parallel with a decreased VEGF-A 189/VEGF-A 121 balance in plaques [less ▲]

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See detailThe CORALS project: simulated Cosmic Radiations and Alternative Splicing.
Lambert, Charles ULg; Battout, S.; Van Oostveldt, P. et al

Conference (2009)

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See detailAltered expression of angiogenesis and lymphangiogenesis markers in the uninvolved skin of plaque-type psoriasis
Henno, Audrey ULg; Blacher, Silvia ULg; Lambert, Charles ULg et al

in British Journal of Dermatology (2009), 160(3), 581-90

Background Vascular alterations are significant events in the pathomechanism of psoriasis. A disorder in the mechanisms regulating skin angiogenesis and lymphangiogenesis could participate in the ... [more ▼]

Background Vascular alterations are significant events in the pathomechanism of psoriasis. A disorder in the mechanisms regulating skin angiogenesis and lymphangiogenesis could participate in the pathogenesis of the disease. Objectives To quantify differences in the expression of angiogenesis and lymphangiogenesis growth factors, receptors, coreceptors as well as their antagonists in the uninvolved skin of patients with psoriasis compared with the skin of nonpsoriatic volunteers. Methods Skin biopsies were collected from the involved skin of 13 patients with untreated plaque-type psoriasis, from their nonlesional skin at distance from the lesions and from the skin of 16 healthy volunteers. The mRNA steady-state level of keratins 10, 14 and 16, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), vimentin, collagen I and IV, proliferating cell nuclear antigen, the various splice variants of vascular endothelial growth factor, VEGF-A, VEGF-C and VEGF-D, their receptors VEGFR1, VEGFR2 and VEGFR3, neuropilin (NRP)-1 and its soluble forms, NRP-2, semaphorin 3A and prox-1, was measured by reverse transcription–polymerase chain reaction. Immunohistochemistry was performed for Ki-67, von Willebrand factor and D2-40. Blood and lymphatic vessel density, area and distance from epidermis were estimated by morphological analysis coupled to an original computer-assisted method of quantification. Results Skin from healthy volunteers and nonlesional skin from patients with psoriasis displayed similar histological, morphometric and proliferative features. However, a significant overexpression of VEGFR3, the VEGF-A isoform VEGF121, soluble 12 NRP-1 and GAPDH was observed in the nonlesional psoriatic skin as compared with that of normal volunteers. Conclusions These data point to significant differences in the blood and lymphatic vascular transcriptome between the clinically normal-appearing skin of patients with psoriasis and the skin of volunteers without psoriasis. [less ▲]

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See detailVEGF111 : Dr Jekyll et Mr Hyde ?
Lambert, Charles ULg; Mineur, Pierre ULg; Nusgens, Betty ULg

in Medecine Sciences : M/S (2008), 24(6-7), 579-80

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See detailHuman bone marrow adipocytes block granulopoiesis through neuropilin-1-induced granulocyte colony-stimulating factor inhibition.
Belaid-Choucair, Zakia ULg; Lepelletier, Yves; Poncin, Géraldine ULg et al

in Stem Cells (2008), 26(6), 1556-64

Adipocytes are part of hematopoietic microenvironment, even though up to now in humans, their role in hematopoiesis is still questioned. We have previously shown that accumulation of fat cells in femoral ... [more ▼]

Adipocytes are part of hematopoietic microenvironment, even though up to now in humans, their role in hematopoiesis is still questioned. We have previously shown that accumulation of fat cells in femoral bone marrow (BM) coincides with increased expression of neuropilin-1 (NP-1), while it is weakly expressed in hematopoietic iliac crest BM. Starting from this observation, we postulated that adipocytes might exert a negative effect on hematopoiesis mediated through NP-1. To test this hypothesis, we set up BM adipocytes differentiated into fibroblast-like fat cells (FLFC), which share the major characteristics of primitive unilocular fat cells, as an experimental model. As expected, FLFCs constitutively produced macrophage colony stimulating factor and induced CD34(+) differentiation into macrophages independently of cell-to-cell contact. By contrast, granulopoiesis was hampered by cell-to-cell contact but could be restored in transwell culture conditions, together with granulocyte colony stimulating factor production. Both functions were also recovered when FLFCs cultured in contact with CD34(+) cells were treated with an antibody neutralizing NP-1, which proved its critical implication in contact inhibition. An inflammatory cytokine such as interleukin-1 beta or dexamethasone modulates FLFC properties to restore granulopoiesis. Our data provide the first evidence that primary adipocytes exert regulatory functions during hematopoiesis that might be implicated in some pathological processes. Disclosure of potential conflicts of interest is found at the end of this article. [less ▲]

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See detailNewly identified biologically active and proteolysis-resistant VEGF-A isoform VEGF111 is induced by genotoxic agents
Mineur, Pierre ULg; Colige, Alain ULg; Deroanne, Christophe ULg et al

in Journal of Cell Biology (2007), 179(6), 1261-1273

Ultraviolet B and genotoxic drugs induce the expression of a vascular endothelial growth factor A (VEGF-A) splice variant (VEGF111) encoded by exons 1-4 and 8 in many cultured cells. Although not detected ... [more ▼]

Ultraviolet B and genotoxic drugs induce the expression of a vascular endothelial growth factor A (VEGF-A) splice variant (VEGF111) encoded by exons 1-4 and 8 in many cultured cells. Although not detected in a series of normal human and mouse tissue, VEGF111 expression is induced in MCF-7 xenografts in nude mice upon treatment by camptothecin. The skipping of exons that contain proteolytic cleavage sites and extracellular matrix-binding domains makes VEGF111 diffusible and resistant to proteolysis. Recombinant VEGF111 activates VEGF receptor 2 (VEGF-R2) and extracellularly regulated kinase 1/2 in human umbilical vascular endothelial cells and porcine aortic endothelial cells expressing VEGF-R2. The mitogenic and chemotactic activity and VEGF111's ability to promote vascular network formation during embyonic stem cell differentiation are similar to those of VEGF121 and 165. Tumors in nude mice formed by HEK293 cells expressing VEGF111 develop a more widespread network of numerous small vessels in the peritumoral tissue than those expressing other isoforms. Its potent angiogenic activity and remarkable resistance to proteolysis makes VEGF111 a potential adverse factor during chemotherapy but a beneficial therapeutic tool for ischemic diseases. [less ▲]

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