Loss of osteoglycin promotes angiogenesis in limb ischaemia mouse models via modulation of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 signalling pathway
Loss of osteoglycin promotes angiogenesis in limb ischaemia mouse models via modulation of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 signalling pathway
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骨甘氨酸缺失通过调节血管内皮生长因子和血管内皮生长因子受体2信号通路促进肢体缺血小鼠模型的血管生成
DOI：
10.1093/cvr/cvw220
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发表时间：
2017-01-01
影响因子：
10.8
通讯作者：
Gao, Ping-Jin
中科院分区：
文献类型：
--
作者：
Wu, Qi-Hong;Ma, Yu;Gao, Ping-Jin
在最近的研究中，目的是在心血管疾病中含义，目的是其对心血管疾病的影响。但是，OGN和血管生成之间的关系仍然未知。因此，我们旨在研究OGN对缺血诱导的血管生成的影响并解决潜在的机制。方法和结果在肢体缺血小鼠模型中降低了OGN的表达。 OGN敲除（KO）小鼠用于进一步了解OGN缺血后的作用。 OGN KO小鼠股动脉连接后的灌注恢复速率高于野生型（WT）小鼠。在OGN KO小鼠中，缺血性肢体的胃肌肌肉中的毛细血管密度也更高。此外，与WT小鼠相比，来自OGN KO小鼠的离体主动脉环外植体表现出更强的血管生成发芽。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。相反，OGN过表达抑制了HUVEC激活。机械研究表明，OGN与血管内皮生长因子受体2（VEGFR2）相关联，并负调节血管内皮生长因子（VEGF）和VEGFR2的相互作用，从而负面调节VEGFR2及其下游信号通路的激活。一致地，通过VEGFR2抑制作用消除了OGN KO的促血管生成作用，支持VEGFR2信号传导在OGN介导的调节血管生成功能调节中的关键作用。CONCONCENCLUSIONSOGN在负调节缺血诱导的con ube ube-devegf-dever-dever-dever-dever-dever-dever-decy-decrienting andfy-dever-decy-decty andfy-deffr2 and andy the and conty and conty and conty and conty and conty and conty to concenty扮演着关键作用。迁移。因此，OGN可能是缺血性血管疾病的新型治疗靶点。
Objective 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.Methods and results 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.Conclusions 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.