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。