Sonic hedgehog mediates a novel pathway of PDGF-BB-dependent vessel maturation.
Recruitment of mural cells (MCs), namely pericytes and smooth muscle cells (SMCs), is essential to improve the maturation of newly formed vessels. Sonic hedgehog (Shh) has been suggested to promote the formation of larger and more muscularized vessels, but the underlying mechanisms of this process have not yet been elucidated. We first identified Shh as a target of platelet-derived growth factor BB (PDGF-BB) and found that SMCs respond to Shh by upregulating extracellular signal-regulated kinase 1/2 and Akt phosphorylation. We next showed that PDGF-BB-induced SMC migration was reduced after inhibition of Shh or its signaling pathway. Moreover, we found that PDGF-BB-induced SMC migration involves Shh-mediated motility. In vivo, in the mouse model of corneal angiogenesis, Shh is expressed by MCs of newly formed blood vessels. PDGF-BB inhibition reduced Shh expression, demonstrating that Shh is a target of PDGF-BB, confirming in vitro experiments. Finally, we found that in vivo inhibition of either PDGF-BB or Shh signaling reduces NG2(+) MC recruitment into neovessels and subsequently reduces neovessel life span. Our findings demonstrate, for the first time, that Shh is involved in PDGF-BB-induced SMC migration and recruitment of MCs into neovessels and elucidate the molecular signaling pathway involved in this process.
INSERM Cardiovascular Adaptation to Ischemia, U1034, Pessac, France;
Qinyu
Q
Yao
Marie-Ange
MA
Renault
Candice
C
Chapouly
Soizic
S
Vandierdonck
Isabelle
I
Belloc
Béatrice
B
Jaspard-Vinassa
Jean-Marie
JM
Daniel-Lamazière
Muriel
M
Laffargue
Aksam
A
Merched
Claude
C
Desgranges
Alain-Pierre
AP
Gadeau
D000818:Animals; D000077214:Becaplermin; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology*; D003315:Cornea / Q000098:blood supply; D053823:Hedgehog Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020286:Pericytes / Q000166:cytology / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D053823:Hedgehog Proteins; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D000077214:Becaplermin