Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2871-2877
© 1999 American Heart Association, Inc.
Vascular Biology |
eNOS Gene Transfer Inhibits Smooth Muscle Cell Migration and MMP-2 and MMP-9 Activity
From the Department of Anatomy and Cell Biology, The University of Iowa College of Medicine, Iowa City.
Correspondence to Ramesh C. Bhalla, PhD, Department of Anatomy and Cell Biology, The University of Iowa College of Medicine, Iowa City, IA 52242. E-mail ramesh-bhalla{at}uiowa.edu
Abstract—Vascular smooth muscle cell (SMC) migration is a critical step in the development of neointima after angioplasty. Matrix metalloproteinases (MMPs) degrade the basement membrane and the extracellular matrix, facilitating SMC migration. Transfer of the endothelial nitric oxide synthase (eNOS) gene to the injury site inhibits neointima formation. Neither the signaling pathways leading to NO-mediated inhibition of SMC migration and proliferation nor the alterations in these pathways have been characterized. We hypothesize that NO inhibits SMC migration in part by regulating MMP activity. To test this hypothesis, we transfected cultured rat aortic SMCs with replication-deficient adenovirus containing bovine eNOS gene and analyzed the conditioned medium for MMP activity. We observed that eNOS gene transfer significantly (P<0.05) inhibited SMC migration and significantly (P<0.05) decreased MMP-2 and MMP-9 activities in the conditioned medium. Similarly, addition of the NO donor DETA NONOate and 8-bromo-cGMP to the culture medium significantly decreased MMP-2 and MMP-9 activities in the conditioned medium collected 24 hours after treatment. Furthermore, Western blot analysis of the conditioned medium collected from eNOS gene–transfected SMCs showed a significant increase in tissue inhibitor of metalloproteinases-2 (TIMP-2) levels. Our data suggest that NO decreases MMP-2 and MMP-9 activities and increases TIMP-2 secretion, and this shifts the balance of MMP activity, which may favor the inhibition of cell migration because of inhibition of extracellular matrix degradation.
Key Words: endothelial nitric oxide synthase • gene transfer • matrix metalloproteinases • tissue inhibitor of metalloproteinases • cell migration • smooth muscle cells
This article has been cited by other articles:
 |
|
 |
|
  K. Hirschberg, T. Radovits, S. Loganathan, L. Entz, C. J. Beller, M.-L. Gross, P. Sandner, M. Karck, and G. Szabo Selective phosphodiesterase-5 inhibition reduces neointimal hyperplasia in rat carotid arteries after surgical endarterectomy. J. Thorac. Cardiovasc. Surg., June 1, 2009; 137(6): 1508 - 1514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Lubbe, D. S. Zuzga, Z. Zhou, W. Fu, J. Pelta-Heller, R. J. Muschel, S. A. Waldman, and G. M. Pitari Guanylyl Cyclase C Prevents Colon Cancer Metastasis by Regulating Tumor Epithelial Cell Matrix Metalloproteinase-9 Cancer Res., April 15, 2009; 69(8): 3529 - 3536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Suzuki, K. Kimura, H. Shirai, K. Eguchi, S. Higuchi, A. Hinoki, K. Ishimaru, E. Brailoiu, D. N. Dhanasekaran, L. N. Stemmle, et al. Endothelial Nitric Oxide Synthase Inhibits G12/13 and Rho-Kinase Activated by the Angiotensin II Type-1 Receptor: Implication in Vascular Migration Arterioscler. Thromb. Vasc. Biol., February 1, 2009; 29(2): 217 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Won, S.-N. Zhu, M. Chen, A.-M. Teichert, J. E. Fish, C. C. Matouk, M. Bonert, M. Ojha, P. A. Marsden, and M. I. Cybulsky Relative Reduction of Endothelial Nitric-Oxide Synthase Expression and Transcription in Atherosclerosis-Prone Regions of the Mouse Aorta and in an in Vitro Model of Disturbed Flow Am. J. Pathol., November 1, 2007; 171(5): 1691 - 1704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Cummins, N. von Offenberg Sweeney, M. T. Killeen, Y. A. Birney, E. M. Redmond, and P. A. Cahill Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H28 - H42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Garanich, M. Pahakis, and J. M. Tarbell Shear stress inhibits smooth muscle cell migration via nitric oxide-mediated downregulation of matrix metalloproteinase-2 activity Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2244 - H2252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Jayasankar, Y. J. Woo, L. T. Bish, T. J. Pirolli, M. F. Berry, J. Burdick, R. C. Bhalla, R. V. Sharma, T. J. Gardner, and H. L. Sweeney Inhibition of Matrix Metalloproteinase Activity by TIMP-1 Gene Transfer Effectively Treats Ischemic Cardiomyopathy Circulation, September 14, 2004; 110(11_suppl_1): II-180 - II-186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Schieffer, C. Bunte, J. Witte, K. Hoeper, R. H. Boger, E. Schwedhelm, and H. Drexler Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease J. Am. Coll. Cardiol., July 21, 2004; 44(2): 362 - 368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Unthank, K. M. Sheridan, and M. C. Dalsing Collateral Growth in the Peripheral Circulation: A Review Vascular and Endovascular Surgery, July 1, 2004; 38(4): 291 - 313. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Janssens, P. Pokreisz, L. Schoonjans, M. Pellens, P. Vermeersch, M. Tjwa, P. Jans, M. Scherrer-Crosbie, M. H. Picard, Z. Szelid, et al. Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction Circ. Res., May 14, 2004; 94(9): 1256 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-H. Chen and D. L. Wang Nitric Oxide Inhibits Matrix Metalloproteinase-2 Expression via the Induction of Activating Transcription Factor 3 in Endothelial Cells Mol. Pharmacol., May 1, 2004; 65(5): 1130 - 1140. [Abstract] [Full Text]
|
|
|
|
|
|
J. H. von der Thusen, M. L. Fekkes, R. Passier, A.J. van Zonneveld, V. Mainfroid, T. J.C. van Berkel, and E. A.L. Biessen Adenoviral Transfer of Endothelial Nitric Oxide Synthase Attenuates Lesion Formation in a Novel Murine Model of Postangioplasty Restenosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 357 - 362. [Abstract] [Full Text]
|
|
|
|
|
|
F. C. Tanner, T. Largiader, H. Greutert, Z. Yang, and T. F. Luscher Nitric oxide synthase gene transfer inhibits biological features of bypass graft disease in the human saphenous vein J. Thorac. Cardiovasc. Surg., January 1, 2004; 127(1): 20 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. T. Schermuly, K. P. Kreisselmeier, H. A. Ghofrani, H. Yilmaz, G. Butrous, L. Ermert, M. Ermert, N. Weissmann, F. Rose, A. Guenther, et al. Chronic Sildenafil Treatment Inhibits Monocrotaline-induced Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., January 1, 2004; 169(1): 39 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Whelan and G. W. Hart Proteomic Approaches to Analyze the Dynamic Relationships Between Nucleocytoplasmic Protein Glycosylation and Phosphorylation Circ. Res., November 28, 2003; 93(11): 1047 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dixit, D. Zhuang, B. Ceacareanu, and A. Hassid Treatment With Insulin Uncovers the Motogenic Capacity of Nitric Oxide in Aortic Smooth Muscle Cells: Dependence on Gab1 and Gab1-SHP2 Association Circ. Res., November 14, 2003; 93 (10): e113 - e123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Meyrelles, R. V. Sharma, H. Z. Mao, F. M. Abboud, and M. W. Chapleau Modulation of baroreceptor activity by gene transfer of nitric oxide synthase to carotid sinus adventitia Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2003; 284(5): R1190 - R1198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tsuruda, G. Boerrigter, B. K. Huntley, J. A. Noser, A. Cataliotti, L. C. Costello-Boerrigter, H. H. Chen, and J. C. Burnett Jr Brain Natriuretic Peptide Is Produced in Cardiac Fibroblasts and Induces Matrix Metalloproteinases Circ. Res., December 13, 2002; 91(12): 1127 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Okamoto, G. Valacchi, K. Gohil, T. Akaike, and A. van der Vliet S-Nitrosothiols Inhibit Cytokine-Mediated Induction of Matrix Metalloproteinase-9 in Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 463 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh, J. W. Son, J. Y. Ahn, D. K. Jin, H. S. Kim, Y. M. Choi, D. S. Kim, E.-M. Jeong, G. S. Park, I. S. Choi, et al. Comparative Effects of Diet and Statin on NO Bioactivity and Matrix Metalloproteinases in Hypercholesterolemic Patients With Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., September 1, 2002; 22(9): e19 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Federici, R. Menghini, A. Mauriello, M. L. Hribal, F. Ferrelli, D. Lauro, P. Sbraccia, L. G. Spagnoli, G. Sesti, and R. Lauro Insulin-Dependent Activation of Endothelial Nitric Oxide Synthase Is Impaired by O-Linked Glycosylation Modification of Signaling Proteins in Human Coronary Endothelial Cells Circulation, July 23, 2002; 106(4): 466 - 472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sreejayan, Y. Lin, and A. Hassid NO Attenuates Insulin Signaling and Motility in Aortic Smooth Muscle Cells via Protein Tyrosine Phosphatase 1B-Mediated Mechanism Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1086 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
|
|
|
|
|
|
M. V. Gurjar, J. Deleon, R. V. Sharma, and R. C. Bhalla Role of reactive oxygen species in IL-1beta -stimulated sustained ERK activation and MMP-9 induction Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2568 - H2574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. V. Sharma, M. V. Gurjar, and R. C. Bhalla Genome and Hormones: Gender Differences in Physiology: Selected Contribution: Estrogen receptor-alpha gene transfer inhibits proliferation and NF-kappa B activation in VSM cells from female rats J Appl Physiol, November 1, 2001; 91(5): 2400 - 2406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Gurjar, J. DeLeon, R. V. Sharma, and R. C. Bhalla Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells J Appl Physiol, September 1, 2001; 91(3): 1380 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Lee, M. Borhani, T. L. Ennis, G. R. Upchurch Jr, and R. W. Thompson Experimental Abdominal Aortic Aneurysms in Mice Lacking Expression of Inducible Nitric Oxide Synthase Arterioscler. Thromb. Vasc. Biol., September 1, 2001; 21(9): 1393 - 1401. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Hsueh, S. Jackson, and R. E. Law Control of Vascular Cell Proliferation and Migration by PPAR-{gamma}: A new approach to the macrovascular complications of diabetes Diabetes Care, February 1, 2001; 24(2): 392 - 397. [Abstract] [Full Text]
|
|
|
|
|
|
K. M. Channon, H. Qian, and S. E. George Nitric Oxide Synthase in Atherosclerosis and Vascular Injury : Insights From Experimental Gene Therapy Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1873 - 1881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Chassagne, C. Adamy, P. Ratajczak, B. Gingras, E. Teiger, E. Planus, P. Oliviero, L. Rappaport, J.-L. Samuel, and S. Meloche Angiotensin II AT2 receptor inhibits smooth muscle cell migration via fibronectin cell production and binding Am J Physiol Cell Physiol, April 1, 2002; 282(4): C654 - C664. [Abstract] [Full Text] [PDF]
|
|