Published Online
on April 29, 2002

A more recent version of this article appeared on May 7, 2002

This Article Full Text (PDF) All Versions of this Article: 105/18/2185    most recent 01.CIR.0000015856.84385.E9v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsunaga, T. Articles by Chilian, W. M. Search for Related Content PubMed Articles by Matsunaga, T. Articles by Chilian, W. M. Related Collections Angiogenesis

Submitted on November 11, 2001
Revised on February 21, 2002
Accepted on February 25, 2002

Angiostatin Inhibits Coronary Angiogenesis During Impaired Production of Nitric Oxide

Toshiro Matsunaga MD, PhD, Dorothee W. Weihrauch DVM, PhD, Melinda C. Moniz BA, John Tessmer BS, David C. Warltier MD, PhD, and William M. Chilian PhD^*

From the Departments of Physiology and Anesthesiology, the Cardiovascular Center, Medical College of Wisconsin, Milwaukee.

^* To whom correspondence should be addressed. E-mail: chilian{at}mcw.edu.

Background—The in vivo mechanism by which inhibition of NO synthase impairs ischemia-induced coronary vascular growth is unknown. We hypothesized that production of the growth inhibitor angiostatin increases during decreased NO production, blunting angiogenesis and collateral growth.

Methods and Results—Measurements were made in myocardial tissue or interstitial fluid (MIF) from dogs undergoing repetitive coronary occlusions under control conditions or during antagonism of NO synthase (N^G-nitro-L-arginine methyl ester [L-NAME]) for 7, 14, or 21 days. A sham group was instrumented identically but received no occlusions. In controls, capillary density in the ischemic zone increased initially but returned to baseline at the later times. In the L-NAME group, capillary density was lower at 7 days compared with that of controls. MIF from control dogs induced in vitro endothelial tube formation and cell proliferation, significantly greater than that from the L-NAME group. MIF from shams did not stimulate tube formation. In controls or shams, tube formation or cell proliferation did not change after administration of antiangiostatin, but this antibody restored the responses to control levels in the L-NAME group. Angiostatin expression in MIF was increased in the L-NAME group compared with controls and shams. The activities of tissue matrix metalloproteinases (MMPs) MMP-2 and MMP-9, which generate angiostatin, were increased in the L-NAME group.

Conclusions—Inhibition of NO synthase increased expression of angiostatin and activities of MMP-2 and MMP-9. Our findings indicate that angiostatin inhibits coronary angiogenesis during compromised NO production and may underscore the impairment of coronary angiogenesis during endothelial dysfunction.

Key words: growth factors • collateral circulation • metalloproteinases • nitric oxide

This article has been cited by other articles:

				T. R. Nurkiewicz, D. W. Porter, A. F. Hubbs, S. Stone, B. T. Chen, D. G. Frazer, M. A. Boegehold, and V. Castranova Pulmonary Nanoparticle Exposure Disrupts Systemic Microvascular Nitric Oxide Signaling Toxicol. Sci., July 1, 2009; 110(1): 191 - 203. [Abstract] [Full Text] [PDF]

				K Yamahara, K D Min, H Tomoike, K Kangawa, S Kitamura, and N Nagaya Pathological role of angiostatin in heart failure: an endogenous inhibitor of mesenchymal stem-cell activation Heart, February 1, 2009; 95(4): 283 - 289. [Abstract] [Full Text] [PDF]

				T. L. Haas, J. L. Doyle, M. R. Distasi, L. E. Norton, K. M. Sheridan, and J. L. Unthank Involvement of MMPs in the outward remodeling of collateral mesenteric arteries Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2429 - H2437. [Abstract] [Full Text] [PDF]

				D. Weihrauch, H. Xu, Y. Shi, J. Wang, J. Brien, D. W. Jones, S. Kaul, R. A. Komorowski, M. E. Csuka, K. T. Oldham, et al. Effects of D-4F on vasodilation, oxidative stress, angiostatin, myocardial inflammation, and angiogenic potential in tight-skin mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1432 - H1441. [Abstract] [Full Text] [PDF]

				J. C. Frisbee, J. B. Samora, J. Peterson, and R. Bryner Exercise training blunts microvascular rarefaction in the metabolic syndrome Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2483 - H2492. [Abstract] [Full Text] [PDF]

				A. W.Y. Chung, Y. N. Hsiang, L. A. Matzke, B. M. McManus, C. van Breemen, and E. B. Okon Reduced Expression of Vascular Endothelial Growth Factor Paralleled With the Increased Angiostatin Expression Resulting From the Upregulated Activities of Matrix Metalloproteinase-2 and -9 in Human Type 2 Diabetic Arterial Vasculature Circ. Res., July 21, 2006; 99(2): 140 - 148. [Abstract] [Full Text] [PDF]

				E. Toyota, D. C. Warltier, T. Brock, E. Ritman, C. Kolz, P. O'Malley, P. Rocic, M. Focardi, and W. M. Chilian Vascular Endothelial Growth Factor Is Required for Coronary Collateral Growth in the Rat Circulation, October 4, 2005; 112(14): 2108 - 2113. [Abstract] [Full Text] [PDF]

				U. Landmesser, F. Bahlmann, M. Mueller, S. Spiekermann, N. Kirchhoff, S. Schulz, C. Manes, D. Fischer, K. de Groot, D. Fliser, et al. Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans Circulation, May 10, 2005; 111(18): 2356 - 2363. [Abstract] [Full Text] [PDF]

				T. Matsunaga, W. M. Chilian, and K. March Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2042 - H2046. [Abstract] [Full Text] [PDF]

				U. Landmesser, N. Engberding, F. H. Bahlmann, A. Schaefer, A. Wiencke, A. Heineke, S. Spiekermann, D. Hilfiker-Kleiner, C. Templin, D. Kotlarz, et al. Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase Circulation, October 5, 2004; 110(14): 1933 - 1939. [Abstract] [Full Text] [PDF]

				R. Marfella, K. Esposito, F. Nappo, M. Siniscalchi, F. C. Sasso, M. Portoghese, M. Pia Di Marino, A. Baldi, S. Cuzzocrea, C. Di Filippo, et al. Expression of Angiogenic Factors During Acute Coronary Syndromes in Human Type 2 Diabetes Diabetes, September 1, 2004; 53(9): 2383 - 2391. [Abstract] [Full Text] [PDF]

				F. Pipp, S. Boehm, W.-J. Cai, F. Adili, B. Ziegler, G. Karanovic, R. Ritter, J. Balzer, C. Scheler, W. Schaper, et al. Elevated Fluid Shear Stress Enhances Postocclusive Collateral Artery Growth and Gene Expression in the Pig Hind Limb Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1664 - 1668. [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]

				D. Weihrauch, N. L. Lohr, B. Mraovic, L. M. Ludwig, W. M. Chilian, P. S. Pagel, D. C. Warltier, and J. R. Kersten Chronic Hyperglycemia Attenuates Coronary Collateral Development and Impairs Proliferative Properties of Myocardial Interstitial Fluid by Production of Angiostatin Circulation, May 18, 2004; 109(19): 2343 - 2348. [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]

				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]

				D. P. Basile, K. Fredrich, D. Weihrauch, N. Hattan, and W. M. Chilian Angiostatin and matrix metalloprotease expression following ischemic acute renal failure Am J Physiol Renal Physiol, May 1, 2004; 286(5): F893 - F902. [Abstract] [Full Text] [PDF]

				M. L. Wahl, T. L. Moser, and S. V. Pizzo Angiostatin and Anti-angiogenic Therapy in Human Disease Recent Prog. Horm. Res., January 1, 2004; 59(1): 73 - 104. [Abstract] [Full Text]

				K. Kameda, T. Matsunaga, N. Abe, H. Hanada, H. Ishizaka, H. Ono, M. Saitoh, K. Fukui, I. Fukuda, T. Osanai, et al. Correlation of oxidative stress with activity of matrix metalloproteinase in patients with coronary artery disease: Possible role for left ventricular remodelling Eur. Heart J., December 2, 2003; 24(24): 2180 - 2185. [Abstract] [Full Text] [PDF]

				N. P. Fam, S. Verma, M. Kutryk, and D. J. Stewart Clinician Guide to Angiogenesis Circulation, November 25, 2003; 108(21): 2613 - 2618. [Full Text] [PDF]

				W. Gu, D. Weihrauch, K. Tanaka, J. P. Tessmer, P. S. Pagel, J. R. Kersten, W. M. Chilian, and D. C. Warltier Reactive oxygen species are critical mediators of coronary collateral development in a canine model Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1582 - H1589. [Abstract] [Full Text] [PDF]

				R. Koshida, J. Ou, T. Matsunaga, W. M. Chilian, K. T. Oldham, A. W. Ackerman, and K. A. Pritchard Jr Angiostatin: A Negative Regulator of Endothelial-Dependent Vasodilation Circulation, February 18, 2003; 107(6): 803 - 806. [Abstract] [Full Text] [PDF]

				J. P. Cooke and D. W. Losordo Nitric Oxide and Angiogenesis Circulation, May 7, 2002; 105(18): 2133 - 2135. [Full Text] [PDF]