(Circulation. 1998;98:2108-2116.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Vascular Endothelial Growth Factor (VEGF) Expression in Human Coronary Atherosclerotic Lesions
Possible Pathophysiological Significance of VEGF in Progression of Atherosclerosis
From the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (M.I., H.I., K.D., Y.O., N.T., K.T., T.I., J.Y., T.-H.C., K.M., K.N.); Department of Pathology, Osaka City University Medical School (M.U., R.K.); Department of Cardiology, Osaka City General Hospital (T.N.); and Department of Anatomy, Osaka City University Medical School (A.K.), Japan; and the Department of Cardiovascular Pathology, Academic Medical Center, University of Amsterdam, The Netherlands (A.E.B.)
Correspondence to Hiroshi Itoh, MD, PhD, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail hiito{at}kuhp.kyoto-u.ac.jp
Background—Vascular endothelial growth factor (VEGF) is an important angiogenic factor reported to induce migration and proliferation of endothelial cells, enhance vascular permeability, and modulate thrombogenicity. VEGF expression in cultured cells (smooth muscle cells, macrophages, endothelial cells) is controlled by growth factors and cytokines. Hence, the question arises of whether VEGF could play a role in atherogenesis.
Methods and Results—Frozen sections from 38 coronary artery segments were studied. The specimens were characterized as normal with diffuse intimal thickening, early atherosclerosis with hypercellularity, and advanced atherosclerosis (atheromatous plaques, fibrous plaques, and totally occlusive lesions). VEGF expression as well as the expression of 2 VEGF receptors, flt-1 and Flk-1, were studied with immunohistochemical techniques in these samples at the different stages of human coronary atherosclerosis progression. The expression of VEGF mRNA was also studied with reverse transcription–polymerase chain reaction. Normal arterial segments showed no substantial VEGF expression. Hypercellular and atheromatous lesions showed distinct VEGF positivity of activated endothelial cells, macrophages, and partially differentiated smooth muscle cells. VEGF positivity was also detected in endothelial cells of intraplaque microvessels within advanced lesions. In totally occlusive lesions with extensive neovascularization, intense immunostaining for VEGF was observed in accumulated macrophages and endothelial cells of the microvessels. Furthermore, VEGF mRNA expression was detected in atherosclerotic coronary segments but not in normal coronary segments. The immunostainings for flt-1 and Flk-1 were detected in aggregating macrophages in atherosclerotic lesions and also in endothelial cells of the microvessels in totally occlusive lesions.
Conclusions—These results demonstrate distinct expression of VEGF and its receptors (flt-1 and Flk-1) in atherosclerotic lesions in human coronary arteries. Considering the multipotent actions of VEGF documented experimentally in vivo and in vitro, our findings suggest that VEGF may have some role in the progression of human coronary atherosclerosis, as well as in recanalization processes in obstructive coronary diseases.
Key Words: angiogenesis • atherosclerosis • coronary disease • immunohistochemistry • pathology
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 F Belgore, A Blann, D Neil, A S Ahmed, and G Y H Lip Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries J. Clin. Pathol., March 1, 2004; 57(3): 266 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 S. Santos, V. I. Peinado, J. Ramirez, J. Morales-Blanhir, R. Bastos, J. Roca, R. Rodriguez-Roisin, and J. A. Barbera Enhanced Expression of Vascular Endothelial Growth Factor in Pulmonary Arteries of Smokers and Patients with Moderate Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., May 1, 2003; 167(9): 1250 - 1256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 K. Yamahara, H. Itoh, T.-H. Chun, Y. Ogawa, J. Yamashita, N. Sawada, Y. Fukunaga, M. Sone, T. Yurugi-Kobayashi, K. Miyashita, et al. Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration PNAS, March 18, 2003; 100(6): 3404 - 3409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. Silvestre, N. Kamsu-Kom, M. Clergue, M. Duriez, and B. I. Levy Very-Low-Dose Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Induces an Early and Sustained Increase in Neovascularization in Rat Ischemic Legs J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1038 - 1043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 N. A.Y. Chung, F. Belgore, F. L. Li-Saw-Hee, D. S.G. Conway, A. D. Blann, and G. Y.H. Lip Is the Hypercoagulable State in Atrial Fibrillation Mediated by Vascular Endothelial Growth Factor? Stroke, September 1, 2002; 33(9): 2187 - 2191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
J.M. Cotton, A. Mathur, Y. Hong, A.S. Brown, J.F. Martin, and J.D. Erusalimsky Acute rise of circulating vascular endothelial growth factor-A in patients with coronary artery disease following cardiothoracic surgery Eur. Heart J., June 2, 2002; 23(12): 953 - 959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 R. I. Clyman, S. R. Seidner, H. Kajino, C. Roman, C. J. Koch, N. Ferrara, N. Waleh, F. Mauray, Y. Q. Chen, E. A. Perkett, et al. VEGF regulates remodeling during permanent anatomic closure of the ductus arteriosus Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R199 - R206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|