Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University Heidelberg, Mannheim, Germany.
Angiogenesis. 2009;12(3):251-65. doi: 10.1007/s10456-009-9145-5. Epub 2009 May 15.
Recently, we have shown that Wnt2 is an autocrine growth and differentiation factor for hepatic sinusoidal endothelial cells. As Wnt signaling has become increasingly important in vascular development and cancer, we analyzed Wnt signaling in non-sinusoidal endothelial cells of different vascular origin (HUVEC, HUAEC, HMVEC-LLy). Upon screening the multiple components of the Wnt pathway, we demonstrated lack of Wnt2 expression, but presence of Frizzled-4, one of its receptors, in cultured non-sinusoidal endothelial cells. Treatment of these cells by exogenous Wnt2 induced endothelial proliferation and sprouting angiogenesis in vitro. Upon analysis of Wnt2 tissue expression as a basis for paracrine Wnt2 effects on non-sinusoidal endothelial cells in vivo, Wnt2 was found to be expressed in densely vascularized murine malignant tumors and in wound healing tissues in close proximity to CD31+ endothelial cells. By gene profiling, stanniocalcin-1 (STC1), a known regulator of angiogenesis, was identified as a target gene of Wnt2 signaling in HUVEC down-regulated by Wnt2 treatment. Tumor-conditioned media counter-acted Wnt2 and up-regulated STC1 expression in HUVEC. In conclusion, we provide evidence that Wnt2 acts as an angiogenic factor for non-sinusoidal endothelium in vitro and in vivo whose target genes undergo complex regulation by the tissue microenvironment.
最近，我们已经证明 Wnt2 是肝窦内皮细胞的自分泌生长和分化因子。由于 Wnt 信号在血管发育和癌症中变得越来越重要，我们分析了不同血管来源的非窦内皮细胞（HUVEC、HUAEC、HMVEC-LLy）中的 Wnt 信号。在筛选 Wnt 通路的多个成分后，我们证明了培养的非窦内皮细胞中缺乏 Wnt2 表达，但存在其受体之一 Frizzled-4。外源性 Wnt2 处理这些细胞可诱导内皮细胞增殖和体外血管生成。在分析 Wnt2 组织表达作为旁分泌 Wnt2 对体内非窦内皮细胞的作用基础时，发现 Wnt2 在富含血管的小鼠恶性肿瘤和紧邻 CD31+内皮细胞的伤口愈合组织中表达。通过基因谱分析，发现已知的血管生成调节剂 STC1（stanniocalcin-1）是 HUVEC 中受 Wnt2 处理下调的 Wnt2 信号的靶基因。肿瘤条件培养基可拮抗 Wnt2 并上调 HUVEC 中的 STC1 表达。总之，我们提供了证据表明 Wnt2 在体内和体外作为非窦内皮细胞的血管生成因子发挥作用，其靶基因受组织微环境的复杂调节。
