Activated Notch4 inhibits angiogenesis:: Role of β1-integrin activation
Activated Notch4 inhibits angiogenesis:: Role of β1-integrin activation
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DOI：
10.1128/mcb.22.8.2830-2841.2002
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发表时间：
2002-04-01
影响因子：
5.3
通讯作者：
Karsan, A
中科院分区：
文献类型：
--
作者：
Leong, KG;Hu, XL;Karsan, A
Notch 4是主要在内皮细胞上表达的跨膜受体Notch家族的成员。Notch在各种细胞系统中的激活已显示出调节细胞命运决定。内皮细胞从微血管中发芽或血管生成涉及内皮细胞表型的调节。基于其他Notch家族成员的功能和Notch 4的表达模式，我们推测Notch 4的激活将调节血管生成。使用体外内皮发芽试验，我们表明，在人真皮微血管内皮细胞（HMEC-1）中表达组成型活性Notch 4抑制内皮发芽。我们还表明，激活的Notch 4抑制血管内皮生长因子（VEGF）诱导的血管生成在鸡胚绒毛尿囊膜在体内。激活的Notch 4不会通过纤维蛋白原抑制HMEC-1增殖或迁移。然而，通过胶原蛋白的迁移受到抑制。我们的数据表明，Notch 4细胞表现出增加的β 1-整合素介导的胶原粘附。表达活化的Notch 4的HMEC-1不具有增加的β 1-整联蛋白的表面表达。相反，我们证明Notch 4表达细胞显示β 1-整联蛋白的活性，高亲和力的构象。此外，使用功能激活β 1-整合素抗体，我们证明β 1-整合素的激活足以抑制VEGF诱导的体外内皮发芽和体内血管生成。我们的研究结果表明，组成性Notch 4激活内皮细胞抑制血管生成的一部分，通过促进β 1-整合素介导的粘附到底层基质。
Notch4 is a member of the Notch family of transmembrane receptors that is expressed primarily on endothelial cells. Activation of Notch in various cell systems has been shown to regulate cell fate decisions. The sprouting of endothelial cells from microvessels, or angiogenesis, involves the modulation of the endothelial cell phenotype. Based on the function of other Notch family members and the expression pattern of Notch4, we postulated that Notch4 activation would modulate angiogenesis. Using an in vitro endothelial-sprouting assay, we show that expression of constitutively active Notch4 in human dermal microvascular endothelial cells (HMEC-1) inhibits endothelial sprouting. We also show that activated Notch4 inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis in the chick chorioallantoic membrane in vivo. Activated Notch4 does not inhibit HMEC-1 proliferation or migration through fibrinogen. However, migration through collagen is inhibited. Our data show that Notch4 cells exhibit increased beta1-integrin-mediated adhesion to collagen. HMEC-1 expressing activated Notch4 do not have increased surface expression of beta1-integrins. Rather, we demonstrate that Notch4-expressing cells display beta1-integrin in an active, high-affinity conformation. Furthermore, using function-activating beta1-integrin antibodies, we demonstrate that activation of beta1-integrins is sufficient to inhibit VEGF-induced endothelial sprouting in vitro and angiogenesis in vivo. Our findings suggest that constitutive Notch4 activation in endothelial cells inhibits angiogenesis in part by promoting beta1-integrin-mediated adhesion to the underlying matrix.