INSERM Cardiovascular Adaptation to Ischemia, U1034, Pessac, France;
Blood. 2014 Apr 10;123(15):2429-37. doi: 10.1182/blood-2013-06-508689. Epub 2014 Jan 28.
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.
募集壁细胞（MCs），即周细胞和血管平滑肌细胞（SMCs），对于改善新形成的血管的成熟度至关重要。 Sonic hedgehog（Shh）被认为可以促进更大和更肌化的血管形成，但其作用机制尚未阐明。我们首先确定 Shh 是血小板衍生生长因子 BB（PDGF-BB）的靶标，并发现 SMC 通过上调细胞外信号调节激酶 1/2 和 Akt 磷酸化来响应 Shh。接下来，我们表明 Shh 或其信号通路的抑制减少了 PDGF-BB 诱导的 SMC 迁移。此外，我们发现 PDGF-BB 诱导的 SMC 迁移涉及 Shh 介导的运动。在体内，在角膜血管生成的小鼠模型中，Shh 由新形成的血管的 MCs 表达。PDGF-BB 抑制减少了 Shh 的表达，证明 Shh 是 PDGF-BB 的靶标，证实了体外实验的结果。最后，我们发现体内抑制 PDGF-BB 或 Shh 信号均可减少 NG2（+）MC 募集到新生血管中，并随后减少新生血管的寿命。我们的研究结果首次表明，Shh 参与 PDGF-BB 诱导的 SMC 迁移和 MC 募集到新生血管中，并阐明了该过程中涉及的分子信号通路。
