RESUMEN
Therapeutic angiogenesis is a highly appealing concept for treating tissues that become ischemic due to vascular disease. A major barrier to the clinical translation of angiogenic therapies is that the patients that are in the greatest need of these treatments often have long term disease states and co-morbidities, such as diabetes and obesity, that make them resistant to angiogenic stimuli. In this study, we identified that human patients with type 2 diabetes have reduced levels of glypican-1 in the blood vessels of their skin. The lack of this key co-receptor in the tissue may make the application of exogenous angiogenic growth factors or cell therapies ineffective. We created a novel therapeutic enhancer for growth factor activity consisting of glypican-1 delivered in a nanoliposomal carrier (a "glypisome"). Here, we demonstrate that glypisomes enhance FGF-2 mediated endothelial cell proliferation, migration and tube formation. In addition, glypisomes enhance FGF-2 trafficking by increasing both uptake and endosomal processing. We encapsulated FGF-2 or FGF-2 with glypisomes in alginate beads and used these to deliver localized growth factor therapy in a murine hind limb ischemia model. Co-delivery of glypisomes with FGF-2 markedly increased the recovery of perfusion and vessel formation in ischemic hind limbs of wild type and diabetic mice in comparison to mice treated with FGF-2 alone. Together, our findings support that glypisomes are effective means for enhancing growth factor activity and may improve the response to local angiogenic growth factor therapies for ischemia.
Asunto(s)
Factor 2 de Crecimiento de Fibroblastos/farmacología , Glipicanos/metabolismo , Nanopartículas/química , Neovascularización Fisiológica/efectos de los fármacos , Alginatos/química , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/terapia , Sistemas de Liberación de Medicamentos , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Ácido Glucurónico/química , Células HEK293 , Células HeLa , Ácidos Hexurónicos/química , Miembro Posterior/irrigación sanguínea , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Isquemia/patología , Isquemia/terapia , Cinética , Liposomas , Ratones Obesos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Piel/irrigación sanguínea , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Delivering syndecan-4 with FGF-2 improves the effectiveness of FGF-2 therapy for ischemia in the diabetic disease state. The syndecan-4 proteoliposomes significantly enhance in vitro tubule formation as well as blood perfusion and vessel density in the ischemic hind limbs of diseased ob/ob mice. Syndecan-4 therapy also induces a marked immunomodulation in the tissues, increasing the polarization of macrophages toward the M2 phenotype.