Sonic hedgehog signaling induces vascular smooth muscle cell proliferation via induction of the G1 cyclin-retinoblastoma axis.
OBJECTIVE
Proliferation of vascular smooth muscle cells (VSMCs) is a crucial event in the pathogenesis of intimal hyperplasia, the main cause of restenosis following vascular reconstruction. Here, the impact of sonic hedgehog (Shh)/Gli family zinc finger 2 (Gli2) signaling on VSMC proliferation was assessed.


RESULTS
Increased Shh signaling was detected in VSMCs in the neointima of vein grafts obtained from mice undergoing restenosis. Comparable results were found in primary cultured human VSMCs (hVSMCs) obtained from patients undergoing coronary bypass surgery, which were used to further assess the impacts of Shh signaling on VSMC proliferation. Inhibition of Shh signaling in hVSMCs through treatment with cyclopamine or knockdown of Gli2 results in G(1) arrest and reduced cyclin D1, cyclin E, and phosphorylated retinoblastoma (pRB) levels. In contrast, activation of Shh/Gli2 signaling in hVSMCs results in increased levels of G(1) cyclins and promotes G(1)-S transition. Stimulation of hVSMC proliferation by Shh is abolished by cyclin D1 knockdown.


CONCLUSIONS
Combined, these results demonstrate that Shh/Gli2 signaling stimulates VSMC proliferation via regulation of the G(1) cyclin-retinoblastoma axis and suggest that antagonists that target the Shh pathway may be therapeutically beneficial in the prevention of intimal hyperplasia.
Li
Fenghe
F
Department of Vascular Surgery, 1st Hospital of China Medical University, Shenyang, China.
Duman-Scheel
Molly
M
Yang
Dong
D
Du
Wei
W
Zhang
Jian
J
Zhao
Chenchao
C
Qin
Lingfeng
L
Xin
Shijie
S
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D004195:Disease Models, Animal; D016193:G1 Phase; D006083:Graft Occlusion, Vascular / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D010766:Phosphorylation; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase; D012501:Saphenous Vein / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D015398:Signal Transduction / Q000187:drug effects; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000075746:Zinc Finger Protein Gli2
D019927:Cyclin E; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; C509239:SHH protein, human; C465570:Shh protein, mouse; D014704:Veratrum Alkaloids; D000075746:Zinc Finger Protein Gli2; D019938:Cyclin D1; C000541:cyclopamine