Sustained Delivery of VEGF Maintains Innervation and Promotes Reperfusion in Ischemic Skeletal Muscles Via NGF/GDNF Signaling |
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Authors: | Dmitry Shvartsman Hannah Storrie-White Kangwon Lee Cathal Kearney Yevgeny Brudno Nhi Ho Christine Cezar Corey McCann Erin Anderson John Koullias Juan Carlos Tapia Herman Vandenburgh Jeff W Lichtman David J Mooney |
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Institution: | 1.School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA;2.Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts, USA;3.Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA;4.Department of Pathology, Brown Medical School–Miriam Hospital, Providence, Rhode Island, USA |
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Abstract: | Tissue reinnervation following trauma, disease, or transplantation often presents a significant challenge. Here, we show that the delivery of vascular endothelial growth factor (VEGF) from alginate hydrogels ameliorates loss of skeletal muscle innervation after ischemic injury by promoting both maintenance and regrowth of damaged axons in mice. Nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) mediated VEGF-induced axonal regeneration, and the expression of both is induced by VEGF presentation. Using both in vitro and in vivo modeling approaches, we demonstrate that the activity of NGF and GDNF regulates VEGF-driven angiogenesis, controlling endothelial cell sprouting and blood vessel maturation. Altogether, these studies produce evidence of new mechanisms of VEGF action, further broaden the understanding of the roles of NGF and GDNF in angiogenesis and axonal regeneration, and suggest approaches to improve axonal and ischemic tissue repair therapies. |
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