Extracellular ATP and adenosine as regulators of endothelial cell function (eBook)

Preface 6
Contents 8
Contributors 10
1 Purinergic and Pyriminergic Activation of the Endothelium in Regulation of Tissue Perfusion 13
1.1 Introduction 13
1.2 Regulation of Vascular Tone: Balance Between Contractile and Dilatory Effects 14
1.3 Nucleotide Release in the Vasculature 15
1.3.1 Endothelial Cells 15
1.3.2 Red Blood Cells 15
1.4 Role of Ectonucleotidases in Regulation of Tissue Perfusion 16
1.5 Receptor Subtypes Involved in Endothelial Relaxation 16
1.6 Mediators of Endothelial Dependent Vasodilation: NO, EDHF and PGI2 17
1.7 Mediators of Endothelial Dependent Vasoconstriction: AP4A, UP4A 18
1.8 Extracellular Nucleotides in Physiological Vascular Regulation 18
1.8.1 Retrograde Spreading Dilatation 18
1.8.2 Sympathicolytic Effects Mediated Via Endothelial Activation 19
1.8.3 Reactive Hyperemia 19
1.8.4 The Role of P2 Receptors in Circulatory Shock and Sepsis 19
1.8.5 Hypertension 20
1.8.6 Pulmonary Hypertension 21
1.8.7 Congestive Heart Failure 21
1.9 Conclusion 21
References 21
2 Nucleotides and Novel Signaling Pathways in Endothelial Cells: Possible Roles in Angiogenesis, Endothelial Dysfunction and Diabetes Mellitus 26
2.1 Introduction 26
2.2 P2 Receptors in ECs and Calcium Responses to Extracellular Nucleotides 28
2.3 Extracellular Nucleotide-Initiated Signaling Pathways 30
2.3.1 Extracellular Nucleotides Activate FAK and Induce Cytoskeletal Changes and EC Migration 30
2.3.2 Extracellular Nucleotides and Adenosine Activate AMPK in HUVECs 31
2.3.3 eNOS Activation by Extracellular Nucleotides 33
2.3.4 Effects of Extracellular Nucleotides on ECs Exposed to High Glucose 35
2.3.5 Effects of ATP in Diabetic ApoE-Knockout Mice 35
2.3.6 Other Signaling Pathways Activated by Extracellular Nucleotides in ECs 36
2.3.7 Cross-talk Between Purinergic and Other Signaling Pathways 37
2.4 Conclusions, Hypotheses, and Controversies 38
References 41
3 Extracellular Purines in Endothelial Cell Barrier Regulation 49
3.1 Introduction 49
3.2 Purinoceptor-Mediated Regulation of Endothelial Barrier Function 51
3.2.1 Cell Signaling Pathways Activated Upon Purinoceptor Stimulation 51
3.2.2 Adenosine-Activated Signaling and Endothelial Monolayer Integrity 54
3.2.3 Purinoceptor-Mediated Signaling as a Regulator of Endothelial Integrity at Various Pathological States 55
3.2.4 Down-Regulation (Desensitization) of Purinoceptor-Mediated Signaling 58
3.3 Barrier-Protective Potency of Receptor-Specific Purinergic Agonists 58
References 59
4 The P2Y2 Nucleotide Receptor in Vascular Inflammation and Angiogenesis 66
4.1 Role of P2Y2 Receptors in Vascular Inflammation 66
4.1.1 Introduction 67
4.1.2 P2Y2 Receptor Up-Regulation and Endothelial Expression of Adhesion Molecules: Role in Endothelial Inflammation 67
4.1.3 Potential Role of Nucleotides and P2Y2 Receptors in Neuroinflammation 70
4.1.4 Development of Transgenic Rats Overexpressing the P2Y2 Receptor: A Model to Study Inflammatory Diseases 72
4.2 P2Y2 Receptors in Angiogenesis 73
4.2.1 P2Y2 Receptors and Neovascularization of Atherosclerotic Plaques 73
4.2.2 Chemotactic Effects Mediated by P2Y2 Receptors 74
4.2.3 P2Y2 Receptors in Tumor Angiogenesis 75
References 77
5 Role of Purine-Converting Ecto-Enzymes in Angiogenic Phenotype of Pulmonary Artery Adventitial Vasa Vasorum Endothelial Cells of Chronically Hypoxic Calves 82
5.1 Introduction 82
5.2 Hypoxia-Induced Vascular Remodeling and Vasa Vasorum Angiogenesis 83
5.3 Hypoxia-Induced Vasa Vasorum Neovascularization Represents an Angiogenesis of Systemic Vessels in the Pulmonary Circulation 84
5.4 Cultured PA Adventitial Vasa Vasorum Endothelial Cells is a Novel In Vitro Angiogenic Model System 85
5.5 Extracellular Nucleotides as Important Regulators of Vascular Functions 86
5.6 Sources and Potential Mechanisms of ATP Release into the Extracellular Milieu 87
5.7 Implication of Extracellular ATP for Vascular Diseases 87
5.8 Extracellular ATP and Pulmonary Artery Adventitia 88
5.9 Effects of Extracellular Nucleotides on Angiogenic Responses in Endothelial Cells 88
5.10 Intracellular Signaling Pathways Associated with Extracellular ATP-Induced Vasa Vasorum Angiogenesis 91
5.11 Purine-Converting Ecto-Enzymes and Their Role in the Regulation of Vascular Homeostasis 92
5.12 Potential Role of Purine-Converting Enzymes in Modulating Angiogenic Potential of VVEC 93
5.13 Conclusion and Perspectives 96
References 97
6 Stimulation of Wound Revascularization by Adenosine Receptor Activation 103
6.1 Introduction 103
6.2 Adenosine Receptor Expression and Function on Dermal Microvascular Endothelial Cells 105
6.3 Adenosine Receptor Activation Promotes Angiogenesis In Vitro 109
6.4 Adenosine A2A Receptor Activation Stimulates both Angiogenesis and Vasculogenesis In Vivo 111
6.4.1 Adenosine Receptor Activation Promotes Wound Vasculogenesis 114
6.5 Contribution of the Fibrinolytic System to the Angiogenic Effect of Adenosine 115
6.6 Conclusion 116
References 117
7 Hypoxia-Inducible Factors and Adenosine Signaling in Vascular Growth 121
7.1 Introduction 121
7.2 Endothelial Cells in Vascular Growth and Development 122
7.3 Hypoxia and Hypoxia-Inducible Transcription Factors 122
7.4 HIFs in Vascular Growth and Development 124
7.5 Hypoxia and Adenosine 124
7.6 Adenosine and Adenosine Receptors in Vascular Growth and Development 127
7.7 Conclusions 128
References 128
8 Regulated Extracellular Nucleotide Metabolism and Function at the Mucosa 133
8.1 Nucleotide Metabolism at the Mucosa 133
8.2 Role of NTPDases (CD39 and CD39-Like)/5-Ectonucleotidase (CD73) Enzymes 134
8.3 Physiological and Pathophysiologic Influences of Nucleotide Metabolites 135
8.4 Transcriptional Regulation of CD39, CD73 and Adenosine Receptors 138
8.5 Therapeutic Considerations for Targeting Nucleotide Metabolism 140
8.6 Conclusion 142
References 142
9 Cell Surface ATP Synthase: A Potential Target for Anti-Angiogenic Therapy 147
9.1 Introduction 147
9.1.1 F1 F0 ATP Synthase Structure and Mechanism 148
9.1.2 Cell Surface F1 F0 ATP Synthase 148
9.2 ATP Synthase and Angiogenesis 151
9.2.1 Receptor for Angiostatin 151
9.2.2 Target for Anti-Angiogenic Treatment 153
9.2.3 pH Regulation: Potential Mechanism for the Anti-Angiogenic Effect of ATP Synthase Inhibition 155
9.3 ATP Synthase and Endothelial Cell Response to Shear Stress 156
9.4 Coupling Factor 6 159
9.5 Endothelial Monocyte-Activating Polypeptide II 160
9.6 Remaining Questions 161
References 164
10 ATP Release Via Connexin Hemichannels Controls Intercellular Propagation of Ca2+ Waves in Corneal Endothelial Cells 168
10.1 Introduction 168
10.1.1 Corneal Endothelium 169
10.1.2 Intercellular Signaling Coordinates Function of the Corneal Endothelium 169
10.1.3 Mechanisms of Intercellular Signaling 173
10.1.4 Mechanisms of GJIC and PIC 173
10.1.4.1 Cx Gap Junctions Mediate GJIC 173
10.1.4.2 Hemichannel-Mediated ATP Release can Produce PIC 175
10.2 AIM 177
10.3 PIC in BCEC 178
10.3.1 IC in BCEC Consists of GJIC and PIC 178
10.3.2 Mechanism of PIC in BCEC 178
10.3.2.1 PIC is Mediated Via Purinergic Signaling 178
10.3.2.2 Mechanism of ATP Release 181
10.3.3 Regulation of PIC 183
10.3.3.1 PIC is Inhibited by Histamine and Thrombin 183
10.3.3.2 Effect of Thrombin on PIC is Inhibited by Adenosine 187
10.3.3.3 Mechanism of Effect of Effects of Thrombin and Adenosine on Intercellular Communication 187
10.4 Discussion 189
10.4.1 Contribution of Cx Hemichannels Towards IC in BCEC 189
10.4.2 Effect of Histamine and Thrombin on PIC in BCEC 190
10.4.3 IC Via ATP in Different Cell Types 192
10.4.4 Physiological and Pathological Significance of PIC in Corneal Endothelium and Other Cell Types 194
References 196
11 Pregnancy Induced Reprogramming of Endothelial Function in Response to ATP: Evidence for Post Receptor Ca2+ Signaling Plasticity 203
11.1 Background 204
11.2 Investigating Differences in P2Y Receptors, G Protein Alpha Subunits and Phospholipase C B3 Expression in P-UAEC Vs. NP-UAEC 206
11.3 IP3 as a Regulator of the Sustained Phase [Ca2+]i Response to ATP 207
11.4 Comparison of the Dose-Dependent Effects of 2-APB and U73122 on [Ca2+]i and eNOS Activity 207
11.5 2-APB as an Effective Inhibitor of Ca2+ Signaling and NO Production in Endothelial Cells Freshly Isolated from the Luminal Surface of the UA Ex Vivo 209
11.6 The Case for TRPC Channels as Mediators of CCE in UAEC 210
11.7 Evidence for Enhanced TRPC3-IP3R-2 Functional Interaction in P-UAEC 211
11.8 Evidence that UA Endothelial Cells Communicate and Coordinate Their Function Via Gap Junctions 212
11.9 Evidence for Expression of CX43 in UAEC and its Role in Mediating Cell Synchronization Through Formation of CX43 Gap Junctions 213
11.10 Reprogramming of the UA Endothelial Cells Also Occurs at the Level of the Mitochondria 215
11.11 Future Studies 216
References 217
12 Purinergic Signalling in Pancreatic Islet Endothelial Cells 220
12.1 Introduction 220
12.2 ATP and Vascular Endothelium 221
12.2.1 General Aspects on Vascular ATP Signalling 221
12.2.2 External ATP Generates and Propagates Ca2+ Signals in Microvascular Endothelium 221
12.3 ATP and the Pancreas 222
12.3.1 Purinergic Nerves and Pancreas 222
12.3.2 Effects of ATP and Adenosine on Exocrine Pancreatic Arterioles 222
12.3.3 Anatomy of the Pancreatic Islets 222
12.3.4 Islet Vascular Anatomy 223
12.3.5 Blood Flow Direction in the Islets 224
12.3.6 Islet Blood Flow Regulation 226
12.4 Interactions Between Endocrine Cells and Islet Endothelium 226
12.4.1 External ATP is a Regulator of Ca2+ Rises Triggering Pulsatile Insulin Release 227
12.4.2 Purinoceptor-Mediated Ca2+ Rise in Isolated Islet Endothelial Cells and ß-Cells 228
12.4.3 ATP-Induced Ca2+ Signalling Between Islet Endothelium and ß-Cells 230
12.5 Conclusion 231
References 232
Index 237

"Chapter 3 Extracellular Purines in Endothelial Cell Barrier Regulation (S. 39-40)

Nagavedi S. Umapathy, Evgeny A. Zemskov, Agnieszka Jezierska, Irina A. Kolosova, Rudolf Lucas, John D. Catravas, and Alexander D. Verin

Abstract The vascular endothelium is a semi-selective diffusion barrier that regulates a variety of functions including controlling of the passage of macromolecules and fluid between the blood and interstitial fluid. It is well known that loss of this barrier (permeability increase) results in tissue inflammation, the hall mark of inflammatory diseases such as acute lung injury (ALI) and a severe form of it, acute respiratory distress syndrome (ARDS). Apart from ventilation strategies, no standard treatment exists for ALI and ARDS, making the search for novel regulators of endothelial hyperpermeability and dysfunction important. Accumulating data suggest that extracellular purines are promising and physiologically relevant barrier-protective agents.

Purines decrease transendothelial permeability by interacting with cell surface P1 and P2Y purinoceptors belonging to the superfamily of G-protein-coupled receptors (GPCR). Selective activation of endothelial purinoreceptors responsible for barrier protection might form a basis for the treatment of various disorders. The therapeutic potential of purinoreceptors is rapidly expanding field in pharmacology and some selective agonists became recently available. In this review, we demonstrate the comprehensive overview of the purinoceptors expression in the endothelium, their interaction with G-proteins and activation of various signal transduction pathways, which lead to an endothelial barrier enhancement and protection.

Keywords Purinoceptor · Vascular endothelium · G-Protein · Permeability · ATP · Barrier enhancement · VE-cadherin · MLC-phosphatase · GPCR · P2Y · Purines · Adenosine · Protein kinase A · LPS

3.1 Introduction

The vascular endothelium is a semi-selective diffusion barrier between the plasma and interstitial fluid and is critical for normal vessel wall homeostasis. Endothelial permeability is known to be regulated by the balance between centripetal and centrifugal intracellular forces, provided by the contractile machinery and the elements opposing contraction, respectively.

The latter include tethering complexes, responsible for cell-cell and cell-substrate contacts, and systems granting cell rigidity and preventing cell collapse, such as actin filaments, microtubules and intermediate filaments [28]. Some naturally occurring substances such as sphingosine-1-phosphate [27] and the second messenger cAMP [39] are known to enhance the endothelial cells (EC) barrier. Recently, much attention has been given to the therapeutic potential of purinergic agonists and antagonists for the treatment of cardiovascular and pulmonary diseases [4, 14, 75, 97]."