Biology Reference
In-Depth Information
2.1 Introduction
For decades, the endothelium was recognized only as a barrier between blood and
tissues located beneath it. Data collected during the last several years provided evi-
dence that ECs actively participate in many physiological and pathological events.
The endothelium comprises a continuous, stable and quiescent, single cell layer
that lines the vasculature. A growing body of experimental data indicates a central
role for the endothelium in the regulation of vascular homeostasis, local immune or
inflammatory reactions associated with platelet deposition and responses to vascular
injury [27].
Effects of extracellular nucleotides in the vasculature, e.g., modulation of blood
vessel relaxation, have been recognized for many years. However, the molecular
mechanisms underlying the endothelial responses have not been fully elucidated.
Recent advances in the purinergic field were enabled by cloning of P2 receptors and
their detailed pharmacological characterization, followed by identification of signal
transduction pathways initiated by extracellular nucleotides in various tissues/cell
types. The role of particular P2 receptors was further elucidated in studies with
P2 receptor-knockout mice. Published results indicate that extracellular nucleotides
activate several signaling pathways in ECs with outcomes similar to those caused
by other regulatory molecules, such as VEGF or thrombin [16, 47, 79].
There are several mechanisms proposed whereby nucleotides are released from
tissues into extracellular fluids in response to cell activation by various stim-
uli, including hypoxia and stress. These mechanisms include exocytosis from
nucleotide-containing granules [11], efflux through a membrane transport systems
(such as ATP-binding cassette transporters) [9, 83], release by connexin or pan-
nexin hemichannels [48, 89, 93, 101, 103] (also discussed in Chapter 10) and
by plasmalemmal voltage-dependent channels [73, 96]. In addition, nucleotides
can be released as a consequence of cell death or tissue damage. Extracellular
nucleotide levels are also regulated by ecto-enzymes (addressed in Chapter 5), such
as ATP-synthase, nucleoside diphosphate kinase and adenylate kinase [80, 126, 127]
and ecto-NTPDases, which, in concert with CD73 (5
-nucleotidase), metabolize
extracellular nucleotides to adenosine [50, 63, 66, 129].
Extracellular nucleotides act as paracrine or autocrine mediators via activation of
purinergic P2 receptors [15, 16, 39, 90]. Pharmacological, functional, and molec-
ular cloning data have facilitated the classification of P2 receptors into two main
groups: P2Y, G protein-coupled receptors and P2X, ligand-gated ion channels [17,
18]. Eight P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11-P2Y14) and
seven P2X receptors subtypes (P2X1-P2X7) have been described to date. While
activation of P2Y receptors results in Ca
2+
release from intracellular stores, P2X
receptors facilitate the entry of extracellular Ca
2+
[13]. P2X receptors are activated
by ATP, whereas P2Y receptors respond to both purine (ATP, ADP) and pyrimidine
(UTP, UDP, UDP-glucose) nucleotides. Specifically, in human tissues ATP is an
agonist for P2Y2 and P2Y11 receptors, UTP for P2Y2 and P2Y4 receptors, ADP for
P2Y1, P2Y12 and P2Y13 receptors, UDP for the P2Y6 receptor, and UDP-glucose
for the P2Y14 receptor [17]. Activation of P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11
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