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.