KRIT1 Protein Depletion Modifies Endothelial Cell Behavior via Increased Vascular Endothelial Growth Factor (VEGF) Signaling
KRIT1 Protein Depletion Modifies Endothelial Cell Behavior via Increased Vascular Endothelial Growth Factor (VEGF) Signaling
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DOI：
10.1074/jbc.m114.582304
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发表时间：
2014-11-21
影响因子：
4.8
通讯作者：
Glading, Angela J.
中科院分区：
文献类型：
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作者：
DiStefano, Peter V.;Kuebel, Julia M.;Glading, Angela J.
内皮细胞-细胞接触的破坏是许多心血管疾病中的关键事件，也是病理激活的血管内皮的特征。CCM（脑海绵状血管畸形）蛋白家族（KRIT 1（Krev-interaction trapped 1）、PDCD 10和CCM 2）是内皮细胞-细胞接触和血管稳态的关键调节因子。在这里，我们显示了新的调节血管内皮生长因子（VEGF）信号在KRIT 1耗尽的内皮细胞。KRIT 1和PDCD 10的缺失，而不是CCM 2的缺失，增加了核β-连环蛋白信号传导并上调了VEGF-A蛋白表达。在KRIT 1缺失的细胞中，VEGF-A水平增加导致VEGF受体2（VEGFR 2）活化增加，随后细胞骨架组织、迁移和屏障功能发生改变，并导致KRIT 1缺陷动物体内内皮通透性增加。VEGFR 2激活也增加β-连环蛋白磷酸化，但仅部分负责KRIT 1消耗依赖性细胞-细胞接触的破坏。因此，VEGF信号传导有助于改变KRIT 1缺陷细胞中的内皮功能和Krit 1（+/-）小鼠中的微血管通透性;然而，VEGF信号传导可能不是在KRIT 1缺失情况下破坏内皮细胞-细胞接触的唯一贡献者。
Disruption of endothelial cell-cell contact is a key event in many cardiovascular diseases and a characteristic of pathologically activated vascular endothelium. The CCM (cerebral cavernous malformation) family of proteins (KRIT1 (Krev-interaction trapped 1), PDCD10, and CCM2) are critical regulators of endothelial cell-cell contact and vascular homeostasis. Here we show novel regulation of vascular endothelial growth factor (VEGF) signaling in KRIT1-depleted endothelial cells. Loss of KRIT1 and PDCD10, but not CCM2, increases nuclear beta-catenin signaling and up-regulates VEGF-A protein expression. In KRIT1-depleted cells, increased VEGF-A levels led to increased VEGF receptor 2 (VEGFR2) activation and subsequent alteration of cytoskeletal organization, migration, and barrier function and to in vivo endothelial permeability in KRIT1-deficient animals. VEGFR2 activation also increases beta-catenin phosphorylation but is only partially responsible for KRIT1 depletion-dependent disruption of cell-cell contacts. Thus, VEGF signaling contributes to modifying endothelial function in KRIT1-deficient cells and microvessel permeability in Krit1(+/-) mice; however, VEGF signaling is likely not the only contributor to disrupted endothelial cell-cell contacts in the absence of KRIT1.