Desert hedgehog promotes ischemia-induced angiogenesis by ensuring peripheral nerve survival.
BACKGROUND
Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves.


OBJECTIVE
The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia.


RESULTS
We induced hindlimb ischemia in wild-type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle.


CONCLUSIONS
This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.
Institut National de la Santé et de la Recherche Médicale, 1 Avenue de Magellan, Pessac, France. marie-ange.renault@inserm.fr
Marie-Ange
MA
Renault
Candice
C
Chapouly
Qinyu
Q
Yao
Frédéric
F
Larrieu-Lahargue
Soizic
S
Vandierdonck
Annabel
A
Reynaud
Myriam
M
Petit
Béatrice
B
Jaspard-Vinassa
Isabelle
I
Belloc
Elisabeth
E
Traiffort
Martial
M
Ruat
Cécile
C
Duplàa
Thierry
T
Couffinhal
Claude
C
Desgranges
Alain-Pierre
AP
Gadeau
D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000294:innervation; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism; D010525:Peripheral Nerves / Q000166:cytology / Q000502:physiology*; D012583:Schwann Cells / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042683:Angiopoietin-1; D053823:Hedgehog Proteins; D009414:Nerve Growth Factors; D042461:Vascular Endothelial Growth Factor A; C518911:neurotropin 3, mouse