Sustained delivery of VEGF maintains innervation and promotes reperfusion in ischemic skeletal muscles via NGF/GDNF signaling.
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.
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA; Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts, USA.
Dmitry
D
Shvartsman
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
Hannah
H
Storrie-White
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA; Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts, USA.
Kangwon
K
Lee
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
Cathal
C
Kearney
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA; Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts, USA.
Yevgeny
Y
Brudno
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
Nhi
N
Ho
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
Christine
C
Cezar
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
Corey
C
McCann
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA; Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts, USA.
Erin
E
Anderson
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA.
John
J
Koullias
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
Juan Carlos
JC
Tapia
Department of Pathology, Brown Medical School-Miriam Hospital, Providence, Rhode Island, USA.
Herman
H
Vandenburgh
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
Jeff W
JW
Lichtman
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA; Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts, USA. Electronic address: mooneyd@seas.harvard.edu.
David J
DJ
Mooney
D000818:Animals; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000294:innervation*; D020932:Nerve Growth Factor / Q000378:metabolism*; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000627:therapeutic use*; D014945:Wound Healing
D051100:Glial Cell Line-Derived Neurotrophic Factor; D042461:Vascular Endothelial Growth Factor A; D020932:Nerve Growth Factor