edited_Vanhoutte.qxp 25/2/09 03:35 Page 66
Endothelial Dysfunction
inhibition). However, their turnover is accelerated by the cardiovascular observed in cultures of regenerated endothelial cells. Moderately
risk factors mentioned previously. Eventually, these cells undergo increased concentrations of oxLDL reduce the production of EDRF by
apoptosis, are removed by circulating blood and are replaced rapidly by endothelial cells and inhibit endothelium-dependent relaxations to
regenerated endothelial cells. It is still uncertain what the exact serotonin,
83,84
hence the conclusion that the augmented presence in
contribution in this regeneration process is of neighbouring cells freed of regenerated endothelial cells of oxLDL is the cause of the selective loss
the contact inhibition and circulating endothelial progenitor cells.
74–78
in Gi-protein-mediated responses and the resulting inability to respond
to serotonin and thrombin, setting the atherosclerotic process in motion
Whatever their origin, regenerated endothelial cells appear to be (see Figure 2).
dysfunctional. This conclusion is based on experiments performed in
porcine coronary arteries. In this preparation, one month after in vivo It would be naïve to claim that this is the only negative effect of oxLDL
balloon denudation of the endothelium of part of the artery a total that obviously plays a central role in the atherosclerotic process.
85–87
It has
relining of the endothelial surface occurred. However, rings with a direct inhibitory effect on the expression and activity of eNOS.
88,89
It also
endothelium of the previously denuded part of the artery did not fully enhances the activity of arginase, which competes with NO for the
relax to aggregating platelets, serotonin or thrombin, and the remaining common substrate arginine.
90–92
A greater production of superoxide
relaxation was no longer inhibited by pertussis toxin, suggesting that Gi- anions will reduce the bioavailability of NO and increase the levels of
protein-mediated responses are defective in regenerated endothelial peroxynitrite.
89,93–95
A number of other genomic factors and endogenous
cells.
27,29,79
In contrast, relaxation evoked by agonists that employ the Gq- mediators may accelerate or contribute to the atherosclerotic
signalling cascade was normal, implying a selective dysfunction of the Gi- process.
78,96–99
However, the ultimate result is that the endothelial cells
dependent responses in regenerated endothelial cells. This selective cannot produce enough NO in response to platelets and thrombin and
dysfunction was reduced by the chronic intake of ω3-unsaturated fatty allow the inflammatory reaction leading to atherosclerosis.
100
acid and exacerbated by a chronic hypercholesterolaemic diet, which
resulted in the occurrence of typical atherosclerotic lesions in the area of Conclusions
previous denudation.
46,60
These observations prompted the conclusion (at Normal endothelial cells respond to aggregating platelets and thrombin by
least by the author and his colleagues) that the dysfunction of regenerated releasing NO. This key endothelial mediator relaxes the underlying vascular
endothelial cells is the first step allowing the atherosclerotic process. smooth-muscle cells and immediately inhibits the platelet aggregation
process. It also inhibits the expression of adhesion molecules, and thus the
Further work to analyse the molecular mechanisms underlying the adhesion and penetration of white blood cells. NO prevents the growth
dysfunction of regenerated endothelial cells was performed on primary and proliferation of vascular smooth-muscle cells, reduces the production
cultures (with all the limitations of cell culture studies, in terms of and action of endothelin-1 production and limits the oxidation of LDL.
relevance to the intact organism) derived from either regenerated or Ageing, insults to the coronary endothelial layer (including lifestyle factors
native endothelium.
78,80–82
The cultures derived from regenerated such as the Western diet, pollution and smoking) or diseases facilitating
endothelium had the appearance and markers of senescent cells, had a cardiovascular events (diabetes and hypertension) create a vicious circle in
reduced expression and activity of eNOS, produced more oxygen- which damaged endothelial cells undergo apoptosis and new ones are
derived free radicals, took up more modified low-density lipoprotein regenerated. However, the function of these regenerated cells differs from
cholesterol (LDL) and generated more oxidised LDL (oxLDL). However, that of native endothelial cells, leading to accelerated cell senescence and
the presence of Gi-proteins was comparable in the two cell types. Those abnormal production of NO and facilitating the inflammatory reaction
phenotypic and functional changes are in line with the genomic changes leading to atherosclerosis. ■
1. Furchgott RF, Zawadzki JV, The obligatory role of endothelial Autonomic Nerves and Endothelium, Raven Press: New York, 2002;4:A8–A17.
cells in the relaxation of arterial smooth muscle by 1988:427–36. 19. Félétou M, Vanhoutte PM, Endothelial dysfunction: a
acetylcholine, Nature, 1980;288:373–6. 8. Moncada S, Nitric oxide in the vasculature:physiology and multifaceted disorder, The Wiggers Award Lecture, Am J Physiol
2. De Mey JG, Claeys M, Vanhoutte PM, Endothelium-dependent pathophysiology, Ann NY Acad Sci, 1997;811:60–67. Heart Circ Physiol, 2006;291:H985–H1002.
inhibitory effects of acetylcholine, adenosine triphosphate, 9. Vanhoutte PM, The endothelium: modulator of vascular 20. Lüescher TF, Tanner FC, Tschudi MR, Noll G, Endothelial
thrombin and arachidonic acid in the canine femoral artery, J smooth-muscle tone, N Engl J Med, 1988;319:512–13. dysfunction in coronary artery disease, Annu Rev Med,
Pharmacol Exp Ther, 1982;222:166–73. 10. Furchgott RF, Vanhoutte PM, Endothelium-derived relaxing and 1993;44:395–418.
3. Cohen RA, Shepherd JT, Vanhoutte PM, Inhibitory role of the contracting factors, FASEB J, 1989;3:2007–17. 21. Vanhoutte PM, Say NO to ET, J Autonom Nervous System,
endothelium in the response of isolated coronary arteries to 11. Lüscher TF, Vanhoutte PM, The Endothelium: Modulator of 2000;81:271–77.
platelets, Science, 1983;221:273–4. Cardiovascular Function, CRC Press, Inc.: Boca Raton, 22. Voetsch B, Jin RC, Loscalzo J, Nitric oxide insufficiency and
4. Rubanyi GM, Lorenz RR, Vanhoutte PM, Bioassay of 1990:1–228. atherothrombosis, Histochemistry and Cell Biology,
endothelium-derived relaxing factor(s) Inactivation by 12. Vanhoutte PM, Félétou M, Taddei S, Endothelium-dependent 2004;122:353–67.
catecholamines, Am J Physiol, 1985;249:H95–H101. contractions in hypertension, Br J Pharmacol, 23. Cohen RA, Shepherd JT, Vanhoutte PM, Vasodilatation
5. Rubanyi GM, Vanhoutte PM, Superoxide anions and hyperoxia 2005;144:449–58. mediated by the coronary endothelium in response to
inactivate endothelium-derived relaxing factors, Am J Physiol, 13. Feletou M, Vanhoutte PM, EDHF: The Complete Story, CRC aggregating platelets, Bibl Cardiol, 1984;38:35–42.
1986;250:H822–H827. Taylor and Francis: Boca Raton, 2006:1–298. 24. Houston DS, Shepherd JT, Vanhoutte PM, Adenine nucleotides,
6. Furchgott RF, Studies on relaxation of rabbit aorta by sodium 14. Félétou M, Vanhoutte P, EDHF: where are we now? serotonin, and endothelium-dependent relaxations to platelets,
nitrite: the basis for the proposal that acid-activatable inhibitory Arteriosclerosis, thrombosis, and vascular biology, Arterioscler Am J Physiol, 1985;248:H389–95.
factor from bovine retractor penis is inorganic nitrite and the Thromb Vasc Biol, 2006;26:1215–25. 25. Houston DS, Shepherd JT, Vanhoutte PM, Aggregating human
endothelium-derived relaxing factor is nitric oxide. In: 15. Félétou M, Vanhoutte PM, Endothelium-dependent platelets cause direct contraction and endothelium-dependent
Vanhoutte PM (ed) Vasodilatation: Vascular Smooth Muscle, hyperpolarizations:past beliefs and present facts, Ann Med, relaxation of isolated canine coronary arteries Role of serotonin,
Peptides, Autonomic Nerves and Endothelium, Raven Press: New 2007;39:495–516. thromboxane A2, and adenine nucleotides, J Clin Invest,
York, 1988:401–14. 16. Vanhoutte PM, Endothelial dysfunction in hypertension, J 1986;78:539–44.
7. Ignarro LJ, Byrns RE, Wood KS, Biochemical and Hypertens, 1996;14:S83–S93. 26. Shimokawa H, Kim P, Vanhoutte PM, Endothelium-dependent
pharmacological properties of endothelium-derived relaxing 17. Vanhoutte PM, Endothelial dysfunction and atherosclerosis, Eur relaxation to aggregating platelets in isolated basilar arteries of
factor and its similarity to nitric oxide radical. In: Vanhoutte PM Heart J, 1997;18:E19–E29. control and hypercholesterolemic pigs, Circ Res,
(ed), Vasodilatation: Vascular Smooth Muscle, Peptides, 18. Vanhoutte PM, Ageing and endothelial dysfunction, Eur Heart J, 1988;63:604–12.
66 ASIA-PACIFIC CARDIOLOGY
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84