Department of Vascular Biology & Tumorangiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
PLoS One. 2013 Jul 9;8(7):e68033. doi: 10.1371/journal.pone.0068033. Print 2013.
Protein kinase D isoenzymes (PKDs, Prkds) are serine threonine kinases that belong to the CAMK superfamily. PKD1 is expressed in endothelial cells and is a major mediator of biological responses downstream of the VEGFRs that are relevant for angiogenesis such as endothelial cell migration, proliferation and tubulogenesis in vitro. PKDs also play a critical role in tumor development and progression, including tumor angiogenesis. However, given the plethora of signaling modules that drive angiogenesis, the precise role of PKD1 in both physiological and tumor angiogenesis in vivo has not been worked out so far. This study aimed at dissecting the contribution of PKD1 to physiological blood vessel formation, PKD1 was found to be widely expressed during zebrafish development. As far as physiological angiogenesis was concerned, morpholino-based silencing of PKD1 expression moderately reduced the formation of the intersomitic vessels and the dorsal longitudinal anastomotic vessel in tg(fli1:EGFP) zebrafish. In addition, silencing of PKD1 resulted in reduced formation of the parachordal lymphangioblasts that serves as a precursor for the developing thoracic duct. Interestingly, tumor angiogenesis was completely abolished in PKD1 morphants using the zebrafish/tumor xenograft angiogenesis assay. Our data in zebrafish demonstrate that PKD1 contributes to the regulation of physiological angiogenesis and lymphangiogenesis during zebrafish development and is essential for tumor angiogenesis.
蛋白激酶 D 同工酶（PKDs，Prkds）是丝氨酸苏氨酸激酶，属于 CAMK 超家族。PKD1 在血管内皮细胞中表达，是 VEGFR 下游生物学反应的主要介质，对于血管生成如内皮细胞迁移、增殖和体外小管形成具有重要作用。PKDs 还在肿瘤的发生和发展中发挥关键作用，包括肿瘤血管生成。然而，鉴于驱动血管生成的信号模块众多，PKD1 在体内生理和肿瘤血管生成中的确切作用迄今尚未阐明。本研究旨在剖析 PKD1 对生理血管形成的贡献，结果发现 PKD1 在斑马鱼发育过程中广泛表达。就生理血管生成而言，PKD1 的表达通过基于 morpholino 的沉默适度减少了 tg(fli1:EGFP)斑马鱼的体节间血管和背侧纵向吻合血管的形成。此外，沉默 PKD1 导致发育中的胸导管前体——脊索旁淋巴胚基的形成减少。有趣的是，在斑马鱼/肿瘤异种移植血管生成测定中，PKD1 形态发生体完全消除了肿瘤血管生成。我们在斑马鱼中的数据表明，PKD1 有助于调节斑马鱼发育过程中的生理血管生成和淋巴管生成，并且对于肿瘤血管生成是必需的。
