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Arteriogenesis – Molecular Regulation, Pathophysiology and Therapeutics I Elisabeth Deindl, Wolfgang Schaper (Editors) Arteriogenesis – Molecular Regulation, Pathophysiology and Therapeutics I Shaker Verlag Aachen 2011 Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available in the Internet at http://dnb.d-nb.de. Copyright Shaker Verlag 2011 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publishers. Printed in Germany. ISBN 978-3-8322-9797-8 ISSN 0945-0890 Shaker Verlag GmbH • P.O. BOX 101818 • D-52018 Aachen Phone: 0049/2407/9596-0 • Telefax: 0049/2407/9596-9 Internet: www.shaker.de • e-mail: [email protected] i Foreword iii Preface vii Contributors ix CHAPTER 1 1 J. E. FABER, X. DAI and J. LUCITTI CHAPTER 2 ! " # $% 23 F. LE NOBLE CHAPTER 3 $% " # & ' 39 L. C. NAPP and F. P. LIMBOURG CHAPTER 4 # & % " # ( ) 67 W. SCHAPER CHAPTER 5 & % 75 C. TROIDL, K. TROIDL, J.I. PAGEL, E. DEINDL and W. SCHAPER CHAPTER 6 !# * + , $ - .+ 89 J. L. UNTHANK, T. L. HAAS AND S. J. MILLER CHAPTER 7 # 121 T. ZIEGELHOEFFER AND E. DEINDL ii CHAPTER 8 % %0& # & 133 T. TRENKWALDER, R. HINKEL AND C. KUPATT CHAPTER 9 , " + * % 145 A.A. HELLINGMAN, L. SEGHERS, P.H.A. QUAX AND V. VAN WEEL CHAPTER 10 * "" % 155 R. HAVERSLAG, S. GRUNDMANN AND I. E. HOEFER CHAPTER 11 % 1 167 A.M. VAN DER LAAN, J.J. PIEK AND N. VAN ROYEN CHAPTER 12 - # 2 & # 179 N. PAGONAS, I. BUSCHMANN, W. SCHAPER AND E. BUSCHMANN CHAPTER 13 & # 191 E. DEINDL AND W. SCHAPER $3 ! - 195 iii +4+" Anecdotal observations about the existence of a bypass circulation in the presence of an arterial obstruction, spontaneous or induced, exist since a long time. It may have started in the Royal deer park of King George where Dr. Hunter occluded vessels feeding the deer’s antler and where the site of occlusion was bypassed by collateral vessels without disturbing the growth of the majestic trophy. Centuries later post mortem studies in humans showed that most hearts are endowed with collateral vessels even in the absence of arterial occlusions, notably the human heart. The descriptive part of research culminated in the work of Fulton [1, 2] who showed the marked enlargement of pre-existing collaterals in human hearts in the presence of arterial occlusive disease. Dr. Fultons impressive angiograms were, apart from his scientific insights, the results of technical refinements, i.e., the use of a contrast material with high density for “soft” X-rays and 3-D viewing. About a decade later in-vivo coronary angiography took off and showed for the first time coronary collaterals in the beating heart, and cases were reported where these vessels had enlarged just in time to prevent an infarct. The important life and tissue-saving role of collaterals was questioned, again a decade later, when angiographers showed that the degree of collateralization correlated with the degree of coronary disease [3, 4], and the erroneous conclusion was drawn that collaterals were rather a bad omen for the downhill course of the disease. This was finally straightened out by studies showing the beneficial effect of collaterals [5]. Basic science became interested in the mechanisms of vascular growth and studies on the rate of growth, the functional capacity, the structure and ultra-structure appeared, because it was obvious that this new knowledge was potentially useful to design new types of therapy, which would benefit patients [6]. However, the interest in vascular research suffered setbacks by allegedly easier and more profitable types of therapy that consisted also of bypasses but this time produced by surgeons, or by eliminating occlusions and stenoses by balloon dilatation and stent deployment at the hands of cardiologists. Only when the stents became occluded, interest in vascular research soared again [7]. Another impediment to “Arteriogenesis”, as research into collateral vessel development was now called, was the flood of publications that followed the claim by Dr. Folkman [8] that with the advent of vascular growth factor the scourges of mankind, i.e., arteriosclerosis and cancer, could be cured by application of one single principle: angiogenesis and its antidote, anti-angiogenesis. Since this almost coincided with the discovery that genetic targeting of the newly discovered vascular endothelial growth factor (VEGF) was embryonic lethal [9], research in endothelial biology received an enormous boost, almost completely neglecting the fact that, at least in arterial disease with tissue ischemia, no shortage of endothelial cells exists and that diseased arteries cannot be replaced by capillaries. Clinical studies using vascular growth factors remained inconclusive in arterial disease [10, 11] and growth factors were not included into the armamentarium of standard therapies. Antiangiogenic therapy in cancer did also not live up to initial expectations [12]. In spite of these impediments arteriogenesis has made great strides forward and we know now that bone marrow derived cells, in particular monocytes, play an essential role [13, 14]. We know now the principal players in the field, thanks to the availability of genetically altered mice. We know that increased fluid shear stress [15, 16], as it occurs in pre-existent arteriolar collaterals as a consequence of an acute occlusion, is the primary physical stimulus, which is responded to by changes in the activity of numerous ion channels, in the up-regulation of NO- producing enzymes [17] and in gene expression. We do not know enough about the molecular signaling that originates from the activated endothelium to the smooth muscles in the media, the major players in arteriogenesis, because their multiplication and remodeling results in the vessel enlargement by a factor of up to 10-fold its original diameter and tissue mass (depending on species and organ supplied and size of occluded artery). The smooth muscles of the media, stimulated somehow by signals from the activated endothelium, produce monocyte chemoattracting protein-1 (MCP-1) [18], which is responsible for the accumulation of monocytes in the wider adventitial space of the developing vessel. Surprisingly, NO plays also a defining role [17]. Surprising, because NO is an anti-mitogen for smooth muscles [19], the most important players in arteriogenesis. However, L-NAME, a non-specific inhibitor of iv all NO producing enzymes, prevents arteriogenesis and the double knock-out of eNOS+iNOS seconds that. Can we now hope that we have come closer to the development of a new therapeutic principle applicable to human patients? Yes, we can! However, we have to overcome strong competition and perhaps even adversaries. Any new drug or vector has to be superior to the well-established revascularization procedures of the surgeons and cardiologists. Industry has to be convinced that it is worthwhile to invest into vascular research again. Again, because most pharmaceutical companies had closed their labs for cardiovascular research in favor of the development of high priced anti-cancer drugs. However, there is hope, but only when we succeed in the complete unraveling of the pathways that rule the development of arterial bypasses, which would enable us to find the limiting step that had escaped evolutionary selection pressure and that we have to stimulate to better Mother Nature. Wolfgang Schaper References [1] Fulton WF. The Dynamic Factor in Enlargement of Coronary Arterial Anastomoses, and Paradoxical Changes in the Subendocardial Plexus. Br Heart J 1964 Jan;26:39-50. [2] Fulton WF. Anastomotic Enlargement and Ischaemic Myocardial Damage. Br Heart J 1964 Jan;26:1-15. [3] Helfant RH, Kemp HG, Gorlin R. Coronary atherosclerosis, coronary collaterals, and their relation to cardiac function. Ann Intern Med 1970 Aug;73(2):189-93. [4] Helfant RH, Vokonas PS, Gorlin R. Functional importance of the human coronary collateral circulation. N Engl J Med 1971 Jun 10;284(23):1277-81. [5] Charney R, Cohen M. The role of the coronary collateral circulation in limiting myocardial ischemia and infarct size. Am Heart J 1993 Oct;126(4):937-45. [6] Schaper W, Schaper J. Arteriogenesis. Boston, Dordrecht, London: Kluwer Acadenic Publishers 2004. [7] Simons M. VEGF and restenosis: the rest of the story. Arterioscler Thromb Vasc Biol 2009 Apr;29(4):439-40. [8] Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res 1986 Feb;46(2):467-73. [9] Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996 Apr 4;380(6573):435-9. [10] Henry TD, Annex BH, McKendall GR, et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 2003 Mar 18;107(10):1359- 65. [11] Henry TD, Rocha-Singh K, Isner JM, et al. Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease. Am Heart J 2001 Nov;142(5):872-80. [12] Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008 Aug;8(8):592-603. [13] Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998 Jan 1;101(1):40- 50. [14] Ito WD, Arras M, Winkler B, Scholz D, Schaper J, Schaper W. Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion. Circ Res 1997 Jun;80(6):829-37. v [15] Pipp F, Boehm S, Cai WJ, et al. Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb.
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