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Protrudin 调节 FAK 活化、内皮细胞迁移和血管生成
Cellular and Molecular Life Sciences
(
IF
6.2
)
Pub Date : 2022-04-04
, DOI:
10.1007/s00018-022-04251-z
Amita Arora
1
,
Annukka M Kivelä
1
,
Ling Wang
2,
3
,
Rimante Minkeviciene
1
,
Juuso H Taskinen
1
,
Birong Zhang
4,
5
,
Annika Koponen
1
,
Jing Sun
4,
5
,
Michiko Shirane
6
,
You Zhou
4,
5
,
Pirta Hotulainen
1
,
Camilla Raiborg
2,
3
,
Vesa M Olkkonen
1,
7
Affiliation
- Minerva Foundation Institute for Medical Research, Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
- Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
- Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
- Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan.
- Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
在血管生成过程中,内皮细胞形成突出的芽并朝向血管生成刺激迁移。在这项研究中,我们研究了内质网 (ER) 锚定蛋白 Protrudin 在内皮细胞突出、迁移和血管生成中的作用。我们的研究结果表明,Protrudin 调节原代内皮细胞、人脐静脉内皮细胞 (HUVEC) 中的血管生成管形成。RNA 测序数据分析及其实验验证表明,细胞迁移是受到 Protrudin 敲低的 HUVEC 影响的一个突出的细胞功能。此外,我们的研究结果表明,敲除 Protrudin 可抑制 HUVEC 和人主动脉内皮细胞 (HAEC) 中的粘着斑激酶 (FAK) 活化。与表达 Protrudin 的 HUVEC 相比,这与 Protrudin 敲低后极化磷酸化 FAK 分布的损失有关。Protrudin 的减少还导致 mTOR 的核周积累和 VEGF 介导的 S6K 活化减少。然而,进一步的实验表明,在 Protrudin 敲低细胞中观察到的血管生成抑制不受 mTOR 干扰的影响。因此,我们的研究结果表明,FAK 激活的缺陷及其在 Protrudin 敲低时的异常亚细胞分布与对内皮细胞迁移和血管生成的不利影响有关。此外,具有整体 Protrudin 缺失的小鼠表现出视网膜血管进展减少。总之,我们的结果为 Protrudin 在内皮细胞迁移和血管生成中的新关键作用提供了证据。
"点击查看英文标题和摘要"
Protrudin regulates FAK activation, endothelial cell migration and angiogenesis
During angiogenesis, endothelial cells form protrusive sprouts and migrate towards the angiogenic stimulus. In this study, we investigate the role of the endoplasmic reticulum (ER)-anchored protein, Protrudin, in endothelial cell protrusion, migration and angiogenesis. Our results demonstrate that Protrudin regulates angiogenic tube formation in primary endothelial cells, Human umbilical vein endothelial cells (HUVECs). Analysis of RNA sequencing data and its experimental validation revealed cell migration as a prominent cellular function affected in HUVECs subjected to Protrudin knockdown. Further, our results demonstrate that knockdown of Protrudin inhibits focal adhesion kinase (FAK) activation in HUVECs and human aortic endothelial cells (HAECs). This is associated with a loss of polarized phospho-FAK distribution upon Protrudin knockdown as compared to Protrudin expressing HUVECs. Reduction of Protrudin also results in a perinuclear accumulation of mTOR and a decrease in VEGF-mediated S6K activation. However, further experiments suggest that the observed inhibition of angiogenesis in Protrudin knockdown cells is not affected by mTOR disturbance. Therefore, our findings suggest that defects in FAK activation and its abnormal subcellular distribution upon Protrudin knockdown are associated with a detrimental effect on endothelial cell migration and angiogenesis. Furthermore, mice with global Protrudin deletion demonstrate reduced retinal vascular progression. To conclude, our results provide evidence for a novel key role of Protrudin in endothelial cell migration and angiogenesis.
更新日期:2022-04-04