Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Circ Res. 2011 May 27;108(11):1367-77. doi: 10.1161/CIRCRESAHA.111.244095. Epub 2011 Apr 14.
The transcription factor HOXC9 belongs to the homeobox gene family acting as developmental morphogen in several species. HOXC9 is EXPRESSED in different vascular beds in vivo. Yet vascular functions of HOXC9 have not been studied.
This study was aimed at characterizing HOXC9 functions in human vascular endothelial cells and in zebrafish vascular development.
HOXC9 was abundantly expressed in resting human umbilical vein endothelial cells and was downregulated by hypoxia. Overexpression of HOXC9 inhibited endothelial cell proliferation, migration, and tube formation in vitro. Expression profiling and chromatin immunoprecipitation experiments in human umbilical vein endothelial cells identified interleukin 8 as the major HOXC9 target and demonstrated the direct binding of HOXC9 to the interleukin 8 promotor. HOXC9 overexpression led to reduced endothelial interleukin 8 production, whereas HOXC9 silencing increased interleukin 8. The antimigratory and antiangiogenic effect of HOXC9 overexpression could be rescued by external interleukin 8 administration. Corresponding to the cellular experiments, endothelial-specific overexpression of HOXC9 and morpholino-based interleukin 8 loss-of-function experiments inhibited zebrafish vascular development.
The data identify HOXC9 as an endothelial cell active transcriptional repressor promoting the resting, antiangiogenic endothelial cell phenotype in an interleukin 8-dependent manner.
转录因子 HOXC9 属于同源盒基因家族，在多个物种中作为发育形态发生素发挥作用。HOXC9 在体内不同的血管床中表达。然而，HOXC9 的血管功能尚未得到研究。
本研究旨在研究 HOXC9 在人血管内皮细胞和斑马鱼血管发育中的功能。
HOXC9 在静息的人脐静脉内皮细胞中大量表达，并被低氧下调。HOXC9 的过表达抑制了体外内皮细胞的增殖、迁移和管形成。在人脐静脉内皮细胞中的表达谱和染色质免疫沉淀实验鉴定出白细胞介素 8 是 HOXC9 的主要靶基因，并证明了 HOXC9 与白细胞介素 8 启动子的直接结合。HOXC9 的过表达导致内皮细胞白细胞介素 8 产生减少，而 HOXC9 的沉默则增加了白细胞介素 8 的产生。HOXC9 过表达的抗迁移和抗血管生成作用可以通过外部白细胞介素 8 给药来挽救。与细胞实验相对应，内皮细胞特异性过表达 HOXC9 和基于 morpholino 的白细胞介素 8 功能丧失实验抑制了斑马鱼血管发育。
数据表明 HOXC9 是一种内皮细胞活性转录抑制剂，以白细胞介素 8 依赖的方式促进静止、抗血管生成的内皮细胞表型。
