43 - Extracellular Nucleotides and Nucleosides as Autocrine and Paracrine Regulators within the Vasculature

Summary

The normal vascular endothelium provides a barrier that separates blood cells and plasma factors from highly reactive elements of the deeper layer of the vessel wall. It maintains blood fluidity and flow by inhibiting coagulation and platelet activation and promoting fibrinolysis (1). These properties are governed by important, specific thromboregulatory mechanisms that include the release of prostacyclin (2), the generation of nitric oxide (NO) (3), and the expression of heparan sulfate (4), together with the expression of natural anticoagulants such as tissue factor pathway inhibitor or thrombomodulin and fibrinolytic mechanisms involving tissue plasminogen activator (1). These properties of the endothelium and antithrombotic pathways are addressed elsewhere in this volume. This chapter focuses on those key biological activities of the vasculature that have been identified recently and shown to be ectonucleotide catalysts that generate the respective nucleosides through phosphohydrolysis (5,6).

Extracellular nucleotides (e.g.,ATP, ADP, UTP, and UDP) are released by leukocytes, platelets, and endothelial cells (ECs) in the blood, where they serve as extracellular signals (7). These mediators bind themultiple type-2 purinergic/pyrimidinergic (P2Y1–14 and P2X1–7) receptors on platelets, endothelium, vascular smooth muscle cells (VSMCs), and leukocytes (8). The 15 defined and characterized P2-receptors of the P2Y and P2X families have different specificities and have been shown to transmit signals from extracellular nucleotides, as discussed later. These receptors trigger and mediate short-term (acute) processes affecting cellular metabolism, NO release, adhesion, activation, and migration together with other more protracted developmental responses, such as cell proliferation, differentiation, and apoptosis (9–11).