Publication

Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF(164)

Résumé

Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF(164) was fused to a sequence derived from alpha 2-plasmin inhibitor (alpha(2)-PI1-8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An alpha(2)-PI1-8-fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-alpha(2)-PI1-8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin-alpha(2)-PI1-8-VEGF(164) allowed exquisitely dose-dependent angiogenesis: concentrations >= 25 mu g/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01-5.0 mu g/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-alpha(2)-PI1-8-VEGF(164) was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis.

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Concepts associés (38)
Facteur de croissance de l’endothélium vasculaire
vignette|L’endothélium vasculaire Le facteur de croissance de l’endothélium vasculaire (en anglais Vascular endothelial growth factor, VEGF) est une protéine jouant un rôle dans le fonctionnement du corps humain. Il a été isolé en 1989 et les trois premiers types sont rapidement identifiés ainsi que son rôle sécrétoire. C'est une protéine dont le rôle dans l'organisme est de déclencher la formation de nouveaux vaisseaux sanguins (angiogenèse) qui est nécessaire pour accompagner la croissance des tissus et le développement des organes du corps humain.
Angiogenèse
L’angiogenèse est le processus de croissance de nouveaux vaisseaux sanguins à partir de vaisseaux préexistants. C'est un processus physiologique normal, que l'on retrouve notamment lors du développement embryonnaire ; mais il peut être pathologique, étant primordial dans la croissance des tumeurs malignes et le développement des métastases. L'hypothèse de l'angiogenèse dans le processus cancéreux a été décrite pour la première fois en 1971.
Cicatrisation
La cicatrisation se présente sous deux aspects : un phénomène de régénération : on parle alors du processus par lequel se réparent les lésions des tissus et des organes (plaie, brûlures) ; un phénomène de consolidation ou de réconciliation d'éléments auparavant unis et qui avaient été séparés. On distingue la cicatrisation "de première intention", qui se produit spontanément et rapidement quand les bords de la plaie sont rapprochés ; et la cicatrisation "de seconde intention", dans le cas contraire, qui nécessite un traitement dermatologique (pommade, solution.
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