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Purinergic P2Y 2 receptors modulate endothelial sprouting
Cellular and Molecular Life Sciences ( IF 6.2 ) Pub Date : 2019-07-05 , DOI: 10.1007/s00018-019-03213-2
Severin Mühleder 1, 2, 3 , Christiane Fuchs 2, 4, 5 , José Basílio 6 , Dorota Szwarc 2, 4 , Karoline Pill 1, 2 , Krystyna Labuda 1, 2 , Paul Slezak 1, 2 , Christian Siehs 7 , Johannes Pröll 2, 8, 9 , Eleni Priglinger 1, 2 , Carsten Hoffmann 10 , Wolfgang G Junger 1, 11 , Heinz Redl 1, 2 , Wolfgang Holnthoner 1, 2
Affiliation  

Abstract

Purinergic P2 receptors are critical regulators of several functions within the vascular system, including platelet aggregation, vascular inflammation, and vascular tone. However, a role for ATP release and P2Y receptor signalling in angiogenesis remains poorly defined. Here, we demonstrate that blood vessel growth is controlled by P2Y2 receptors. Endothelial sprouting and vascular tube formation were significantly dependent on P2Y2 expression and inhibition of P2Y2 using a selective antagonist blocked microvascular network generation. Mechanistically, overexpression of P2Y2 in endothelial cells induced the expression of the proangiogenic molecules CXCR4, CD34, and angiopoietin-2, while expression of VEGFR-2 was decreased. Interestingly, elevated P2Y2 expression caused constitutive phosphorylation of ERK1/2 and VEGFR-2. However, stimulation of cells with the P2Y2 agonist UTP did not influence sprouting unless P2Y2 was constitutively expressed. Finally, inhibition of VEGFR-2 impaired spontaneous vascular network formation induced by P2Y2 overexpression. Our data suggest that P2Y2 receptors have an essential function in angiogenesis, and that P2Y2 receptors present a therapeutic target to regulate blood vessel growth.



中文翻译:


嘌呤能 P2Y 2 受体调节内皮出芽


 抽象的


嘌呤能 P2 受体是血管系统内多种功能的关键调节因子,包括血小板聚集、血管炎症和血管张力。然而,ATP 释放和 P2Y 受体信号传导在血管生成中的作用仍不清楚。在这里,我们证明血管生长是由 P2Y 2受体控制的。内皮出芽和血管形成显着依赖于P2Y 2表达,并且使用选择性拮抗剂抑制P2Y 2阻断微血管网络生成。从机制上讲,内皮细胞中 P2Y 2的过度表达诱导促血管生成分子 CXCR4、CD34 和血管生成素-2 的表达,同时 VEGFR-2 的表达减少。有趣的是,P2Y 2表达升高引起 ERK1/2 和 VEGFR-2 的组成型磷酸化。然而,除非P2Y 2持续表达,否则用P2Y 2激动剂UTP刺激细胞并不影响出芽。最后,抑制 VEGFR-2 会损害 P2Y 2过表达诱导的自发血管网络形成。我们的数据表明 P2Y 2受体在血管生成中具有重要功能,并且 P2Y 2受体是调节血管生长的治疗靶点。

更新日期:2020-03-06
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