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Underlying mechanisms of decreased collateral formation in patients with Metabolic Syndrome
- Eric Van Belle, Frédéric Mouquet, Sophie Susen, Eric Boulanger, Pierre Vladimir Ennezat, François Cuilleret, Pascal Pigny, Bernadette Hennache, Marie Christine Vantyghem, Jean Dallongeville, Pieter M.A Doevendans, Brigitte Jude, Michel Bertrand, Eric Van Belle. (9 September 2009)
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Negative predictors of collateral formation: Evidence based on novel functional and mechanistic data
- Johannes Waltenberger, Vadim Tchaikovski (9 September 2009)
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Eric Van Belle, Professor CHRU and Université de Lille 2, EA-2693, Lille, France. UMC, Utrecht, The Netherlands, Frédéric Mouquet, Sophie Susen, Eric Boulanger, Pierre Vladimir Ennezat, François Cuilleret, Pascal Pigny, Bernadette Hennache, Marie Christine Vantyghem, Jean Dallongeville, Pieter M.A Doevendans, Brigitte Jude, Michel Bertrand, Eric Van Belle.
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We thank V Tchaikovski and J Waltenberger for their comment upon our manuscript describing the adverse influence of metabolic syndrome (MS) on collateral vessel formation in patients with occluded coronary arteries (1). As they stated, this study is the first to demonstrate a strong and inverse relationship between the presence of the metabolic syndrome and the extent of coronary collateral circulation in humans. It is also the first to demonstrate that smokers have less coronary collaterals in response to coronary occlusion. These observations are important in the context of previous conflicting results; in particular recent publications in which metabolic syndrome and smoking were not identified as predictors of decreased coronary collateral circulation (2,3). However these studies were recognized to have important methodological weaknesses (4). Indeed, while it is known that the growth of collaterals is a time-dependent process occurring only in case of severe ischemia secondary to tight stenoses or occluded vessels, these parameters were not taken into account in those previous publications. The strength of our study was to avoid these pitfalls by investigating a large population (387 patients) including exclusively individuals with occluded coronary vessels and adjusting for the duration of coronary occlusion. We also investigated the potential underlying mechanisms relating the metabolic syndrome to a decreased collateral circulation. In our study, hyperglycemia, insulin-resistance (HOMA-IR), and hypertension were identified as key independent predictors of poor coronary collateral vessel development. At the molecular level, the role of PAI-1 and adiponectin were also investigated. PAI-1 is an inhibitor of fibrinolysis with antiangiogenic properties while adiponectin is an adipocyte-derived cytokine downregulated in patients with metabolic syndrome and known to have angiogenic properties in animals. We demonstrated that higher PAI-1 levels and lower adiponectin levels are associated with less collateral vessel formation. We also provided data on circulating EPCs and demonstrated that the presence of the metabolic syndrome was associated with a lower number of circulating early EPCs. Importantly we also demonstrated that adiponectin could modulate early EPCs ability to repair vascular damage. V Tchaikovski and J Waltenberger in their interesting letter (5) suggest an additional potential mechanism. Based on data recently published by their group (6,7)), they suggest that part of the deleterious effect of MS on collateral circulation could be related to negative functional effects of MS on VEGF-Receptor 1 – mediated monocyte migration. They nicely demonstrated that mobilization of monocytes from diabetic patients was significantly impaired and that this was related to a decreased growth factor transduction of the VEGF pathway secondary to enhanced oxidative stress and increased signalling via RAGE. We agree that monocytes are likely to play an important role in vascular repair. In a recent study (8) we found that early EPCs mobilized after vascular damage induced by angioplasty was closely related to inflammation. The mobilization of monocytes was very similar to the mobilization of early EPCs (8) and was less important in diabetic than in non-diabetic patients (unpublished data). Whether the relation between EPCs, monocytes mobilization and inflammation reflect increased oxidative stress will need further investigation. Taken together the work by V Tchaikovski et al and our work demonstrate the negative impact of Ms on vascular repair and identify potential therapeutic targets to improve the cardiovascular condition of these patients. References: 1) Mouquet F, Cuilleret F, Susen S, Sautiere K, Marboeuf P, Ennezat, McFadden E, Pigny P, Richard F, Hennache B, Vantyghem MC, Bertrand M, Dallongeville J, Jude B, Van Belle E. Metabolic syndrome and collateral vessel formation in patients with documented occluded coronary arteries: association with hyperglycaemia, insulin-resistance, adiponectin and plasminogen activator inhibitor-1. Eur Heart J 2009. 2) Olijhoek JK, Koerselman J, de Jaegere PP, Verhaar MC, Grobbee DE, van der Graaf Y, Visseren FL. Presence of the metabolic syndrome does not impair coronary collateral vessel formation in patients with documented coronary artery disease. Diabetes Care. 2005;28:683-9. 3) Koerselman J, de Jaegere PP, Verhaar MC, van der Graaf Y, Grobbee DE. High blood pressure is inversely related with the presence and extent of coronary collaterals. J Hum Hypertens. 2005;19:809-17. 4) Tayebjee MH, Lip GY, Macfadyen RJ. Is there an association between hypertension and the development of coronary collateral flow? J Hum Hypertens. 2005;19:757-9. 5) Tchaikovski V and Waltenberger J. Negative predictors of collateral fromation: Evidence based on novel functional and mechanistic data. Eur Heart J 2009. 6) Tchaikovski V, Böhmer F-D, Waltenberger J. VEGFR-1 signal transduction defect as the molecular basis of monocyte dysfunction in diabetes mellitus. Eur Heart J 2008;29 (Suppl. 1):242-243. 7) Tchaikovski V, Olieslagers S, Böhmer F-D, Waltenberger J. Diabetes mellitus activates signal transduction pathways resulting in VEGF resistance of human monocytes. Circulation 2009;120:150-159. 8) Marboeuf P, Corseaux D, Mouquet F, Van Belle E, Jude B, Susen S. Inflammation triggers colony forming endothelial cell mobilization after angioplasty in chronic lower limb ischemia. J Thromb Haemost. 2008 Jan;6(1):195-7. No abstract available. Conflict of Interest:None declared |
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Johannes Waltenberger, Professor of Cardiology 6202AZ Maastricht, Netherlands, Vadim Tchaikovski
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Vadim Tchaikovski and Johannes Waltenberger Department of Cardiology, University of Maastricht, Maastricht, The Netherlands Referred to: Mouquet F, Cuilleret F, Susen S, Sautière K, Marboeuf P, Ennezat PV, McFadden E, Pigny P, Richard F, Hennache B, Vantyghem MC, Bertrand M, Dallongeville J, Jude B, Van Belle E. Metabolic syndrome and collateral vessel formation in patients with documented occluded coronary arteries: association with hyperglycaemia, insulin-resistance, adiponectin and plasminogen activator inhibitor-1. European Heart Journal 2009 Vadim Tchaikovski, Department of Cardiology, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands Vadim.tchaikovski@cardio.unimaas.nl Johannes Waltenberger Department of Cardiology, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands j.waltenberger@mumc.nl With interest we read the article by Mouquet and colleagues [1] describing an adverse influence of metabolic syndrome (MS) on collateral vessel formation in patients with occluded coronary arteries. This is the first study to show an adverse effect of MS - and some of its components including dyslipidemia and hyperglycemia - on collateral formation in a cohort of 181 individuals. Likewise, smoking for the first time was documented to negatively and independently correlate with reduced coronary collateralization. On a descriptive level, this study adds evidence to previously published data on the negative effect of certain cardiovascular risk factors on mechanisms of collateral vessel development. However, the links between the current findings and the underlying molecular mechanisms remain to be established. Previous work documented that several individual cardiovascular risk factors have negative functional effects on Vascular Endothelial Growth Factor receptor-1 (VEGFR-1)-mediated monocyte migration. This includes diabetes mellitus [2], smoking [3], and hypercholesterolaemia [4]. The impaired VEGFR-1-mediated monocyte migration is likely to represent a cellular basis of impaired collateral formation as observed in the presence of DM, smoking or MS (reviewed and reported by [1]). Monocytes are important cellular components of collateral formation [5]. Monocytes migrate out of the blood stream and accumulate around the growing collateral vessel [6]. VEGFR-1 is an important mediator of monocyte migration during collateral growth [6, 7]. Different cardiovascular risk factors and components of MS share similar pathophysiological mechanisms such as increased production of reactive oxygen species (oxidative stress) and elevated levels of advanced glycation end products (increased glycation). It is important to note that our laboratory has recently identified a novel pattern of DM-related molecular alterations leading to VEGFR-1 dysfunction in monocytes [8, 9]. These changes include enhanced oxidative stress and increased signaling via RAGE (receptor for advanced glycation end products) leading to unspecific monocyte activation, and - in turn - to VEGFR-1 dysfunction and VEGF resistance. The VEGFR-1 system hereby appears to be more vulnerable than the receptor system for fMLP [8, 9]. These DM-related alterations leading to monocyte dysfunction may provide a basis for the development of novel therapeutic corrections by interfering with molecular oxidation and/or glycation. Indeed, there is experimental evidence that antagonizing oxidative stress in smokers can restitute VEGFR-1 function in monocytes [3]. Taken together, the report by Mouquet et al. on the negative impact of MS on collateral vessel development highlights the detrimental effect of systemic metabolic abnormalities. Impaired cellular function such as monocyte dysfunction, which contributes to impaired collateral development, represents a promising therapeutic target for improving collateral development in MS. References [1] Mouquet F, Cuilleret F, Susen S, Sautiere K, Marboeuf P, Ennezat PV, et al. Metabolic syndrome and collateral vessel formation in patients with documented occluded coronary arteries: association with hyperglycaemia, insulin-resistance, adiponectin and plasminogen activator inhibitor-1. Eur Heart J 2009. [2] Waltenberger J, Lange J, Kranz A. Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: A potential predictor for the individual capacity to develop collaterals. Circulation 2000;102:185-190. [3] Stadler N, Eggermann J, Vöö S, Kranz A, Waltenberger J. Smoking- induced monocyte dysfunction is reversed by vitamin C supplementation in vivo. Arterioscler Thromb Vasc Biol 2007;27:120-126. [4] Czepluch FS, Bergler A, Waltenberger J. Hypercholesterolaemia impairs monocyte function in CAD patients. J Intern Med 2007;261:201-204. [5] Waltenberger J. Growth factor signal transduction defects in the cardiovascular system. Cardiovasc Res 2005;65:574-580. [6] Babiak A, Schumm AM, Wangler C, Loukas M, Wu J, Dombrowski S, et al. Coordinated activation of VEGFR-1 and VEGFR-2 is a potent arteriogenic stimulus leading to enhancement of regional perfusion. Cardiovasc Res 2004;61:789-795. [7] Tchaikovski V, Fellbrich G, Waltenberger J. The molecular basis of VEGFR-1 signal transduction pathways in primary human monocytes. Arterioscler Thromb Vasc Biol 2008;28:322-328. [8] Tchaikovski V, Böhmer F-D, Waltenberger J. VEGFR-1 signal transduction defect as the molecular basis of monocyte dysfunction in diabetes mellitus. Eur Heart J 2008;29 (Suppl. 1):242-243. [9] Tchaikovski V, Olieslagers S, Böhmer F-D, Waltenberger J. Diabetes mellitus activates signal transduction pathways resulting in VEGF resistance of human monocytes. Circulation 2009;120:150-159. Conflict of Interest:None declared |
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