Angiogenesis plays an important role in pathological events such as tumor growth, wound healing and psoriasis. Recent research reveals the contribution of purines and pyrimidines to this process. ATP, ADP, UTP, UDP and adenosine play pivotal signaling roles in these long-term events, mediated through P1 and P2 receptors. Specific to the P2 receptors, physiological effects can be exerted via receptor P2X, which are fast ionotropic receptors that function as cationic-gated channels, and P2Y which are GPCRs. These receptors are coupled to specific cellular functions as diverse as angiogenesis, neurotransmission, wound healing, morphogenesis and apoptosis.
The P2Y family consists of seven functional mammalian P2Y receptors: P2Y1, P2Y2, P2Y4, P2Y5, P2Y6, P2Y11, and P2Y12 with each member displaying ligand preferences and the ability to activate a variety of downstream signaling pathways. For example, P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11 receptors are coupled to the activation of PLC, mobilization of intracellular Ca2+ and activation of PKC whereas the newly cloned P2Y12 receptor couples solely to the inhibition of AC. The P2Y11 receptor is dually coupled to the activation of PLC and AC.
P2Y receptors are expressed ubiquitously, but specific tissue responses are achieved by cell-specific expression profiles. For example, endothelial cells release ATP and UTP during shear stress and hypoxia which acts on P2Y1, P2Y2 and sometimes P2Y4 purinoceptors leading to the production of NO and subsequent vasodilation. ATP and UTP released from endothelial cells stimulate endothelial and smooth muscle cell proliferation via P2Y1, P2Y2, and P2Y4 receptors. Blood-borne platelets possess P2Y1 and P2Y12 ADP-selective purinoceptors. Activation of the P2Y1 receptor alone causes platelet shape change but no aggregation unless the P2Y12 receptor is activated concomitantly. This concomitant activation initiates signaling pathways that ultimately trigger the activation of GPIIB/IIIA which promotes high-affinity binding to fibrinogen and platelet aggregation. Mitogenesis/cell proliferation is another important function of P2Y receptors. P2Y2, P2Y4, P2Y6 and P2Y11 activate various other downstream signaling pathways including PI3K/AKT, PLC/Ca+2 and AC/PKA leading to the activation of transcription factors such as c-Fos, c-Jun, CREB and c-Myc. These factors regulate the expression of genes that are involved in cell proliferation. Since the P2Y receptors are coupled to multiple specific cellular functions, they have a tremendous potential in therapeutic applications.