Sonic Hedgehog induces Notch target gene expression in vascular smooth muscle cells via VEGF-A.
Sonic Hedgehog induces Notch target gene expression in vascular smooth muscle cells via VEGF-A.
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DOI：
10.1161/atvbaha.109.186890
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发表时间：
2009-07
期刊：
影响因子：
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通讯作者：
Cahill PA
中科院分区：
文献类型：
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作者：
Morrow D;Cullen JP;Liu W;Guha S;Sweeney C;Birney YA;Collins N;Walls D;Redmond EM;Cahill PA
Notch、VEGF和Hedgehog（Hh）信号传导通路的组分已经涉及血管形态发生。Notch在介导hedgehog控制成人血管平滑肌（SMC）生长和存活中的作用尚未研究。在培养的SMC中，用重组rShh（3.5 μg/ml）或质粒编码的Shh激活Hh信号增加Ptc 1表达，增强SMC生长和存活，并促进Hairy相关转录因子（Hrt）表达，同时增加VEGF-A水平。这些作用显着逆转后Hh抑制环巴胺。RPMS-1抑制Notch介导的CBF-1/RBP-Jk依赖性信号传导后，Shh诱导的Hrt-3 mRNA刺激和SMC生长和存活减弱，而siRNA敲低Hrt-3抑制SMC生长和存活。重组VEGF-A增加了Hrt-3 mRNA水平，而siRNA敲低则消除了rShh刺激的VEGF-A表达，同时分别抑制Shh诱导的Hrt-3 mRNA水平、增殖细胞核抗原（PCNA）和Notch 1 IC表达的增加。Hedgehog组分在血管损伤后的小鼠颈动脉内膜SMC内表达，伴随着Ptc 1、Gli 2、VEGF-A、Notch 1和Hrt的mRNA的显著增加。Hedgehog通过VEGF-A促进成人SMC中Notch靶基因的协调调节。
Notch, VEGF and components of the Hedgehog (Hh) signaling pathway have been implicated in vascular morphogenesis. The role of Notch in mediating hedgehog control of adult vascular smooth muscle (SMC) growth and survival remains unexplored. In cultured SMC, activation of Hh signaling with recombinant rShh (3.5 μg/ml) or plasmid encoded Shh increased Ptc1 expression, enhanced SMC growth and survival and promoted Hairy-related transcription factor (Hrt) expression while concomitantly increasing VEGF-A levels. These effects were significantly reversed following Hh inhibition with cyclopamine. Shh-induced stimulation of Hrt-3 mRNA and SMC growth and survival was attenuated following inhibition of Notch mediated-CBF-1/RBP-Jk dependent signaling with RPMS-1 while siRNA knockdown of Hrt-3 inhibited SMC growth and survival. Recombinant VEGF-A increased Hrt-3 mRNA levels while siRNA knockdown abolished rShh stimulated VEGF-A expression while concomitantly inhibiting Shh-induced increases in Hrt-3 mRNA levels, proliferating cell nuclear antigen (PCNA) and Notch 1 IC expression, respectively. Hedgehog components were expressed within intimal SMC of murine carotid arteries following vascular injury concomitant with a significant increase in mRNA for Ptc1, Gli2, VEGF-A, Notch 1 and Hrt’s. Hedgehog promotes a coordinate regulation of Notch target genes in adult SMC via VEGF-A.