Institute of Anatomy, University of Bern, Bern, Switzerland.
Center of Molecular Medicine, Medical University Sofia, Sofia, Bulgaria.
J Cell Mol Med. 2019 Jun;23(6):3916-3926. doi: 10.1111/jcmm.14269. Epub 2019 Apr 4.
The precise mechanisms of SDF-1 (CXCL12) in angiogenesis are not fully elucidated. Recently, we showed that Notch inhibition induces extensive intussusceptive angiogenesis by recruitment of mononuclear cells and it was associated with increased levels of SDF-1 and CXCR4. In the current study, we demonstrated SDF-1 expression in liver sinusoidal vessels of Notch1 knockout mice with regenerative hyperplasia by means of intussusception, but we did not detect any SDF-1 expression in wild-type mice with normal liver vessel structure. In addition, pharmacological inhibition of SDF-1/CXCR4 signalling by AMD3100 perturbs intussusceptive vascular growth and abolishes mononuclear cell recruitment in the chicken area vasculosa. In contrast, treatment with recombinant SDF-1 protein increased microvascular density by 34% through augmentation of pillar number compared to controls. The number of extravasating mononuclear cells was four times higher after SDF-1 application and two times less after blocking this pathway. Bone marrow-derived mononuclear cells (BMDC) were recruited to vessels in response to elevated expression of SDF-1 in endothelial cells. They participated in formation and stabilization of pillars. The current study is the first report to implicate SDF-1/CXCR4 signalling in intussusceptive angiogenesis and further highlights the stabilizing role of BMDC in the formation of pillars during vascular remodelling.
SDF-1（CXCL12）在血管生成中的精确机制尚未完全阐明。最近，我们发现 Notch 抑制通过单核细胞的募集诱导广泛的分叶状血管生成，并且与 SDF-1 和 CXCR4 水平的增加相关。在本研究中，我们通过分叶状血管生成显示 Notch1 敲除小鼠肝窦血管中的 SDF-1 表达，但在正常肝血管结构的野生型小鼠中未检测到任何 SDF-1 表达。此外，通过 AMD3100 抑制 SDF-1/CXCR4 信号转导可破坏分叶状血管生长并消除鸡腔血管中的单核细胞募集。相比之下，与对照组相比，重组 SDF-1 蛋白通过增加支柱数量使微血管密度增加了 34%。SDF-1 应用后，渗出单核细胞的数量增加了四倍，而阻断该途径后则减少了两倍。骨髓源性单核细胞（BMDC）响应内皮细胞中 SDF-1 的高表达被募集到血管中。它们参与了支柱的形成和稳定。本研究首次报道 SDF-1/CXCR4 信号在分叶状血管生成中的作用，并进一步强调了 BMDC 在血管重塑过程中形成支柱中的稳定作用。
