Purinergic P2Y2 receptors modulate endothelial sprouting

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 P2Y 2 receptors. Endothelial sprouting and vascular tube formation were significantly dependent on P2Y 2 expression and inhibition of P2Y 2 using a selective antagonist blocked microvascular network generation. Mechanistically, overexpression of P2Y 2 in endothelial cells induced the expression of the proangiogenic molecules CXCR4, CD34, and angiopoietin-2, while expression of VEGFR-2 was decreased. Interestingly, elevated P2Y 2 expression caused constitutive phosphorylation of ERK1/2 and VEGFR-2. However, stimulation of cells with the P2Y 2 agonist UTP did not influence sprouting unless P2Y 2 was constitutively expressed. Finally, inhibition of VEGFR-2 impaired spontaneous vascular network formation induced by P2Y 2 overexpression. Our data suggest that P2Y 2 receptors have an essential function in angiogenesis, and that P2Y 2 receptors present a therapeutic target to regulate blood vessel growth.