| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(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
This article has been cited by other articles:
 |
|
 |
|
  Y. Nakashima, T. N. Wight, and K. Sueishi Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans Cardiovasc Res, July 1, 2008; 79(1): 14 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Kalka and I. Baumgartner Gene and stem cell therapy in peripheral arterial occlusive disease Vascular Medicine, May 1, 2008; 13(2): 157 - 172. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Misra, A. A. Fu, A. Puggioni, K. M. Karimi, J. N. Mandrekar, J. F. Glockner, L. A. Juncos, B. Anwer, A. M. McGuire, and D. Mukhopadhyay Increased shear stress with upregulation of VEGF-A and its receptors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2219 - H2230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cuaz-Perolin, L. Billiet, E. Bauge, C. Copin, D. Scott-Algara, F. Genze, B. Buchele, T. Syrovets, T. Simmet, and M. Rouis Antiinflammatory and Antiatherogenic Effects of the NF-{kappa}B Inhibitor Acetyl-11-Keto-{beta}-Boswellic Acid in LPS-Challenged ApoE-/- Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 272 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Horvath and Y. Zhou Transmyocardial Laser Revascularization and Extravascular Angiogenetic Techniques to Increase Myocardial Blood Flow Card. Surg. Adult, January 1, 2008; 3(2008): 733 - 752. [Full Text]
|
|
|
|
 |
|
 M. Nachtigal, A. Ghaffar, and E. P. Mayer Galectin-3 Gene Inactivation Reduces Atherosclerotic Lesions and Adventitial Inflammation in ApoE-Deficient Mice Am. J. Pathol., January 1, 2008; 172(1): 247 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Barbieri and B. B. Weksler Tobacco smoke cooperates with interleukin-1{beta} to alter {beta}-catenin trafficking in vascular endothelium resulting in increased permeability and induction of cyclooxygenase-2 expression in vitro and in vivo FASEB J, June 1, 2007; 21(8): 1831 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Doyle and N. Caplice Plaque Neovascularization and Antiangiogenic Therapy for Atherosclerosis J. Am. Coll. Cardiol., May 29, 2007; 49(21): 2073 - 2080. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-Y. Chyu and P. K. Shah Choking off Plaque Neovascularity: A Promising Atheroprotective Strategy or A Double-Edged Sword? Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 993 - 995. [Full Text] [PDF]
|
|
|
|
|
|
R. J. Petrovan, C. D. Kaplan, R. A. Reisfeld, and L. K. Curtiss DNA Vaccination Against VEGF Receptor 2 Reduces Atherosclerosis in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1095 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Jaumdally, C. Varma, R. J. Macfadyen, and G. Y.H. Lip Coronary sinus blood sampling: an insight into local cardiac pathophysiology and treatment? Eur. Heart J., April 2, 2007; 28(8): 929 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yla-Herttuala, T. T. Rissanen, I. Vajanto, and J. Hartikainen Vascular Endothelial Growth Factors: Biology and Current Status of Clinical Applications in Cardiovascular Medicine J. Am. Coll. Cardiol., March 13, 2007; 49(10): 1015 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Herrmann, L. O. Lerman, D. Mukhopadhyay, C. Napoli, and A. Lerman Angiogenesis in Atherogenesis Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 1948 - 1957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schmeisser, M. Christoph, A. Augstein, R. Marquetant, M. Kasper, R.C. Braun-Dullaeus, and R.H. Strasser Apoptosis of human macrophages by Flt-4 signaling: Implications for atherosclerotic plaque pathology Cardiovasc Res, September 1, 2006; 71(4): 774 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Saeed, A. J. Martin, R. J. Lee, O. Weber, D. Revel, D. Saloner, and C. B. Higgins MR Guidance of Targeted Injections into Border and Core of Scarred Myocardium in Pigs Radiology, August 1, 2006; 240(2): 419 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, D. Mukhopadhyay, and X. Xu C terminus of RGS-GAIP-interacting protein conveys neuropilin-1-mediated signaling during angiogenesis FASEB J, July 1, 2006; 20(9): 1513 - 1515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Fujita, M. Yoshizumi, Y. Izawa, N. Ali, H. Ohnishi, Y. Kanematsu, K. Ishizawa, K. Tsuchiya, and T. Tamaki Transactivation of Fetal Liver Kinase-1/Kinase-Insert Domain-Containing Receptor by Lysophosphatidylcholine Induces Vascular Endothelial Cell Proliferation Endocrinology, March 1, 2006; 147(3): 1377 - 1385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Pinheiro, C. M. Castro, and V. L. Szejnfeld Low femoral bone mineral density and quantitative ultrasound are risk factors for new osteoporotic fracture and total and cardiovascular mortality: a 5-year population-based study of brazilian elderly women. J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2006; 61(2): 196 - 203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Dulak, S. P Schwarzacher, R. H Zwick, H. Alber, G. Millonig, C. Weiss, H. Hugel, M. Frick, A. Jozkowicz, O. Pachinger, et al. Effects of local gene transfer of VEGF on neointima formation after balloon injury in hypercholesterolemic rabbits Vascular Medicine, November 1, 2005; 10(4): 285 - 291. [Abstract] [PDF]
|
|
|
|
|
|
M. Garcia-Ramirez, J. Martinez-Gonzalez, J. O. Juan-Babot, C. Rodriguez, and L. Badimon Transcription Factor SOX18 Is Expressed in Human Coronary Atherosclerotic Lesions and Regulates DNA Synthesis and Vascular Cell Growth Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2398 - 2403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Baba, Y. Yonemitsu, T. Nakano, M. Onimaru, M. Miyazaki, Y. Ikeda, S. Sumiyoshi, Y. Ueda, M. Hasegawa, I. Yoshino, et al. Cytoplasmic Expression and Extracellular Deposition of an Antiangiogenic Factor, Pigment Epithelium-Derived Factor, in Human Atherosclerotic Plaques Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1938 - 1944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Leppanen, S. Koota, I. Kholova, J. Koponen, C. Fieber, U. Eriksson, K. Alitalo, and S. Yla-Herttuala Gene Transfers of Vascular Endothelial Growth Factor-A, Vascular Endothelial Growth Factor-B, Vascular Endothelial Growth Factor-C, and Vascular Endothelial Growth Factor-D Have No Effects on Atherosclerosis in Hypercholesterolemic Low-Density Lipoprotein-Receptor/Apolipoprotein B48-Deficient Mice Circulation, August 30, 2005; 112(9): 1347 - 1352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Yau, G. Li, Y. Zhang, R. D. Weisel, D. A.G. Mickle, and R.-K. Li Vascular Endothelial Growth Factor Receptor Upregulation in Response to Cell-Based Angiogenic Gene Therapy Ann. Thorac. Surg., June 1, 2005; 79(6): 2056 - 2063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Costa and D. I. Simon Molecular Basis of Restenosis and Drug-Eluting Stents Circulation, May 3, 2005; 111(17): 2257 - 2273. [Full Text] [PDF]
|
|
|
|
|
|
G. A. Krombach, J. G. Pfeffer, S. Kinzel, M. Katoh, R. W. Gunther, and A. Buecker MR-guided Percutaneous Intramyocardial Injection with an MR-compatible Catheter: Feasibility and Changes in T1 Values after Injection of Extracellular Contrast Medium in Pigs Radiology, May 1, 2005; 235(2): 487 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Coats and R. Wadsworth Marriage of resistance and conduit arteries breeds critical limb ischemia Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1044 - H1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Reinhardt, P. Schaarschmidt, A. Bossert, A. Luske, G. Finkenzeller, T. Mertens, and D. Michel Upregulation of functionally active vascular endothelial growth factor by human cytomegalovirus J. Gen. Virol., January 1, 2005; 86(1): 23 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. O'Riain, D. J. Buggy, M. J. Kerin, R. W. G. Watson, and D. C. Moriarty Inhibition of the Stress Response to Breast Cancer Surgery by Regional Anesthesia and Analgesia Does Not Affect Vascular Endothelial Growth Factor and Prostaglandin E2 Anesth. Analg., January 1, 2005; 100(1): 244 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn Vascular Endothelial Growth Factor and Angiogenesis Pharmacol. Rev., December 1, 2004; 56(4): 549 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Zhao, K. Egashira, K.-i. Hiasa, M. Ishibashi, S. Inoue, K. Ohtani, C. Tan, M. Shibuya, A. Takeshita, and K. Sunagawa Essential Role of Vascular Endothelial Growth Factor and Flt-1 Signals in Neointimal Formation After Periadventitial Injury Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2284 - 2289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Sharif, K. Daly, J. Crowley, and T. O'Brien Current status of catheter- and stent-based gene therapy Cardiovasc Res, November 1, 2004; 64(2): 208 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ohtani, K. Egashira, K.-i. Hiasa, Q. Zhao, S. Kitamoto, M. Ishibashi, M. Usui, S. Inoue, Y. Yonemitsu, K. Sueishi, et al. Blockade of Vascular Endothelial Growth Factor Suppresses Experimental Restenosis After Intraluminal Injury by Inhibiting Recruitment of Monocyte Lineage Cells Circulation, October 19, 2004; 110(16): 2444 - 2452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Murdoch, A. Giannoudis, and C. E. Lewis Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues Blood, October 15, 2004; 104(8): 2224 - 2234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Epstein, E. Stabile, T. Kinnaird, C. W. Lee, L. Clavijo, and M. S. Burnett Janus Phenomenon: The Interrelated Tradeoffs Inherent in Therapies Designed to Enhance Collateral Formation and Those Designed to Inhibit Atherogenesis Circulation, June 15, 2004; 109(23): 2826 - 2831. [Full Text] [PDF]
|
|
|
|
|
|
M. Saeed, R. Lee, A. Martin, O. Weber, G. A. Krombach, S. Schalla, M. Lee, D. Saloner, and C. B. Higgins Transendocardial Delivery of Extracellular Myocardial Markers by Using Combination X-ray/MR Fluoroscopic Guidance: Feasibility Study in Dogs Radiology, June 1, 2004; 231(3): 689 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.H. Tayebjee, G.Y.H. Lip, and R.J. MacFadyen Collateralization and the response to obstruction of epicardial coronary arteries QJM, May 1, 2004; 97(5): 259 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
J. Rutanen, P. Leppanen, T. T Tuomisto, T. T Rissanen, M. O Hiltunen, I. Vajanto, M. Niemi, T. Hakkinen, K. Karkola, S. A Stacker, et al. Vascular endothelial growth factor-D expression in human atherosclerotic lesions Cardiovasc Res, October 1, 2003; 59(4): 971 - 979. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
D. J. Lenihan, A. Osman, V. Sriram, J. Aitsebaomo, and C. Patterson Evidence for association of coronary sinus levels of hepatocyte growth factor and collateralization in human coronary disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1507 - H1512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.C Felmeden, A.D Blann, and G.Y.H Lip Angiogenesis: basic pathophysiology and implications for disease Eur. Heart J., April 1, 2003; 24(7): 586 - 603. [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
T. Kobayashi and K. Kamata Short-term insulin treatment and aortic expressions of IGF-1 receptor and VEGF mRNA in diabetic rats Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1761 - H1768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N.A.Y. Chung, C. Lydakis, F. Belgore, A.D. Blann, and G.Y.H. Lip Angiogenesis in myocardial infarction. An acute or chronic process? Eur. Heart J., October 2, 2002; 23(20): 1604 - 1608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
H. Franz Alber, J. Dulak, M. Frick, W. Dichtl, S. Paul Schwarzacher, O. Pachinger, and F. Weidinger Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1951 - 1955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lavie, H. Kraiczi, A. Hefetz, H. Ghandour, A. Perelman, J. Hedner, and P. Lavie Plasma Vascular Endothelial Growth Factor in Sleep Apnea Syndrome: Effects of Nasal Continuous Positive Air Pressure Treatment Am. J. Respir. Crit. Care Med., June 15, 2002; 165(12): 1624 - 1628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
B. S. Conklin, W. Zhao, D.-S. Zhong, and C. Chen Nicotine and Cotinine Up-Regulate Vascular Endothelial Growth Factor Expression in Endothelial Cells Am. J. Pathol., February 1, 2002; 160(2): 413 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
J. Dulak, A. Jozkowicz, M. Frick, H. F. Alber, W. Dichtl, S. P. Schwarzacher, O. Pachinger, and F. Weidinger Vascular endothelial growth factor: angiogenesis, atherogenesis or both? J. Am. Coll. Cardiol., December 1, 2001; 38(7): 2137 - 2138. [Full Text] [PDF]
|
|
|
|
|
|
J. Herrmann, L. O Lerman, M. Rodriguez-Porcel, D. R Holmes Jr., D. M Richardson, E. L Ritman, and A. Lerman Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia Cardiovasc Res, September 1, 2001; 51(4): 762 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Isner, P. R. Vale, J. F. Symes, and D. W. Losordo Assessment of Risks Associated With Cardiovascular Gene Therapy in Human Subjects Circ. Res., August 31, 2001; 89(5): 389 - 400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
|