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Supplemental material, sj-docx-1-tej-10.1177_20417314221119615 for Therapeutic arteriogenesis by factor-decorated fibrin matrices promotes wound healing in diabetic mice by Rosalinda D’Amico, Camilla Malucelli, Andrea Uccelli, Andrea Grosso, Nunzia Di Maggio, Priscilla S Briquez, Jeffrey A Hubbell, Thomas Wolff, Lorenz Gürke, Edin Mujagic, Roberto Gianni-Barrera and Andrea Banfi in Journal of Tissue Engineering

INTRODUCCIÓN: La hidroterapia es un método utilizado en el tratamiento de rehabilitación de diversas enfermedades con un resultado positivo, incluyendo enfermedades del sistema nervioso (SN). Se utiliza en muchos programas de ejercicios y se ha demostrado que reduce los síntomas clínicos de la enfermedad del SN, reduce el dolor y mejora la calidad de vida. El mecanismo de acción de la hidroterapia es omnidireccional; entre otras cosas, tiene un efecto positivo en los mecanismos de la columna vertebral, induce la relajación muscular y afecta a la actividad del sistema nervioso autónomo (SNA).OBJETIVOS: Revisar la literatura publicada en los últimos 10 años, en la que se utilizara la hidroterapia para el tratamiento de la enfermedad de Parkinson comparando su efectividad con el tratamiento convencional en tierra firme.METODOLOGÍA: Se llevó a cabo una revisión sistemática según las directrices de la declaración PRISMA. Se realizó una búsqueda en PubMed, PEDro, Cochrane y Web of Science y se incluyeron aquellos estudios que cumplían los criterios de inclusión, así mismo, se valoró la calidad metodológica.RESULTADOS: Se incluyeron 5 estudios publicados entre 2010 y 2020 que comprueban la eficacia de la hidroterapia frente al tratamiento en tierra firme en la enfermedad de Parkinson.CONCLUSIÓN: El tratamiento mediante hidroterapia parece aportar beneficios adicionales a la terapia en tierra principalmente en el equilibrio y la capacidad motora, pero los resultados no son lo bastante determinantes, por lo que se requieren estudios adicionales para confirmarlos.

Therapeutic angiogenesis, that is, the generation of new vessels by delivery of specific factors, is required both for rapid vascularization of tissue-engineered constructs and to treat ischemic conditions. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis. However, uncontrolled expression can lead to aberrant vascular growth and vascular tumors (angiomas). Major challenges to fully exploit VEGF potency for therapy include the need to precisely control in vivo distribution of growth factor dose and duration of expression. In fact, the therapeutic window of VEGF delivery depends on its amount in the microenvironment around each producing cell rather than on the total dose, since VEGF remains tightly bound to extracellular matrix (ECM). On the other hand, short-term expression of less than about 4 weeks leads to unstable vessels, which promptly regress following cessation of the angiogenic stimulus. Here, we will briefly overview some key aspects of the biology of VEGF and angiogenesis and discuss their therapeutic implications with a particular focus on approaches using gene therapy, genetically modified progenitors, and ECM engineering with recombinant factors. Lastly, we will present recent insights into the mechanisms that regulate vessel stabilization and the switch between normal and aberrant vascular growth after VEGF delivery, to identify novel molecular targets that may improve both safety and efficacy of therapeutic angiogenesis.

© 2015 The Authors. VEGF is widely investigated for therapeutic angiogenesis but while short term delivery is desirable for safety it is insufficient for new vessel persistence jeopardizing efficacy. Here we investigated whether and how VEGF dose regulates nascent vessel stabilization to identify novel therapeutic targets. Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses in SCID mouse muscles. VEGF was abrogated after 10 and 17 days by Aflibercept treatment. Vascular stabilization was fastest with low VEGF but delayed or prevented by higher doses without affecting pericyte coverage. Rather VEGF dose dependently inhibited endothelial Semaphorin3A expression thereby impairing recruitment of Neuropilin 1 expressing monocytes (NEM) TGF ß1 production and endothelial SMAD2/3 activation. TGF ß1 further initiated a feedback loop stimulating endothelial Semaphorin3A expression thereby amplifying the stabilizing signals. Blocking experiments showed that NEM recruitment required endogenous Semaphorin3A and that TGF ß1 was necessary to start the Semaphorin3A/NEM axis. Conversely Semaphorin3A treatment promoted NEM recruitment and vessel stabilization despite high VEGF doses or transient adenoviral delivery. Therefore VEGF inhibits the endothelial Semaphorin3A/NEM/TGF ß1 paracrine axis and Semaphorin3A treatment accelerates stabilization of VEGF induced angiogenesis.