State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Laboratory of Vascular Biology and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cardiovasc Res. 2017 Jan;113(1):70-80. doi: 10.1093/cvr/cvw220. Epub 2016 Oct 23.
Osteoglycin (OGN) has been noted for its implication in cardiovascular disease in recent studies. However, the relationship between OGN and angiogenesis remains unknown. Therefore, we aimed to investigate the effect of OGN on ischaemia-induced angiogenesis and to address the underlying mechanisms.
The expression of OGN was decreased in a limb ischaemia mouse model. OGN knockout (KO) mice were used to further understand the role of OGN after ischaemia. The perfusion recovery rate after femoral artery ligation was higher in OGN KO mice than in wild-type (WT) mice. The capillary density in the gastrocnemius muscle of the ischaemic limb was also higher in OGN KO mice. Moreover, ex vivo aortic ring explants from OGN KO mice exhibited stronger angiogenic sprouting than those from WT mice. In human umbilical vein endothelial cells (HUVECs), OGN knockdown enhanced endothelial cell (EC) activation, including tube formation, proliferation, and migration. In contrast, OGN overexpression inhibited HUVEC activation. Mechanistic studies revealed that OGN associates with vascular endothelial growth factor receptor 2 (VEGFR2) and negatively regulates the interaction of vascular endothelial growth factor (VEGF) and VEGFR2, thereby negatively modulating the activation of VEGFR2 and its downstream signalling pathways. Consistently, the pro-angiogenic effect of OGN KO was abrogated by VEGFR2 inhibition, supporting the critical role of VEGFR2 signalling in OGN-mediated regulation of angiogenic function.
OGN plays a critical role in negatively regulating ischaemia-induced angiogenesis by inhibiting VEGF-VEGFR2 signalling and thereby attenuating EC tube formation, proliferation, and migration. Thus, OGN may be a novel therapeutic target for ischaemic vascular diseases.
最近的研究表明，骨连接蛋白（OGN）与心血管疾病有关。然而，OGN 与血管生成的关系尚不清楚。因此，我们旨在研究 OGN 对缺血诱导的血管生成的影响，并探讨其潜在机制。
在肢体缺血小鼠模型中，OGN 的表达降低。使用 OGN 敲除（KO）小鼠进一步了解缺血后 OGN 的作用。与野生型（WT）小鼠相比，OGN KO 小鼠股动脉结扎后的灌注恢复率更高。缺血肢体比目鱼肌中的毛细血管密度在 OGN KO 小鼠中也更高。此外，来自 OGN KO 小鼠的主动脉环外植体在体外表现出比 WT 小鼠更强的血管生成发芽能力。在人脐静脉内皮细胞（HUVEC）中，OGN 敲低增强了内皮细胞（EC）的激活，包括管形成、增殖和迁移。相比之下，OGN 过表达抑制了 HUVEC 的激活。机制研究表明，OGN 与血管内皮生长因子受体 2（VEGFR2）结合，并负调控血管内皮生长因子（VEGF）与 VEGFR2 的相互作用，从而负调控 VEGFR2 及其下游信号通路的激活。一致地，VEGFR2 抑制消除了 OGN KO 的促血管生成作用，支持 VEGFR2 信号在 OGN 介导的血管生成功能调节中的关键作用。
OGN 通过抑制 VEGF-VEGFR2 信号通路在负调控缺血诱导的血管生成中发挥关键作用，从而减弱 EC 管形成、增殖和迁移。因此，OGN 可能是缺血性血管疾病的一种新的治疗靶点。
