(Circulation. 2000;101:2345.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Abnormal Aortic Valve Development in Mice Lacking Endothelial Nitric Oxide Synthase
From the Division of Cardiology, Terrence Donnelly Heart Center, St Michael’s Hospital, University of Toronto, Ontario, Canada.
Correspondence to Duncan J. Stewart, MD, Dexter H.C. Man Chair and Director of Cardiology, University of Toronto, Terrence Donnelly Heart Center, St Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada, M5B 1W8. E-mail stewartd{at}smh.toronto.on.ca
Background—Endothelium-derived nitric oxide (NO) is produced by an oxidative reaction catalyzed by endothelial NO synthase (eNOS). NO plays a crucial role in controlling cell growth and apoptosis, as well as having well-characterized vasodilator and antithrombotic actions. More recently, endothelium-derived NO was shown to be involved in postdevelopmental vascular remodeling and angiogenesis, as well as in the formation of limb vasculature during embryogenesis. Therefore, we investigated the role of endothelium-derived NO during cardiovascular development using mice deficient in eNOS.
Methods and Results—We examined the hearts of 12 mature eNOS-deficient and 26 mature wild-type mice. Five of the mature eNOS-deficient mice had a bicuspid aortic valve; none of the 26 wild-type animals exhibited identifiable valvular or cardiac abnormalities. Immunohistochemical analysis revealed prominent eNOS expression localized to the endothelium lining the valve cusps of the aorta in mature wild-type mice; expression was localized to the myocardium and endothelial cell monolayer lining the valve leaflets in the developing embryo.
Conclusions—These results show a strong association between eNOS deficiency and the presence of a bicuspid aortic valve; they provide the first molecular insight into one of the most common types of congenital cardiac abnormality.
Key Words: nitric oxide • endothelium • mice, knockout • heart defects, congenital • valves
This article has been cited by other articles:
 |
|
 |
|
  A.-M. Teichert, J. A. Scott, G. B. Robb, Y.-Q. Zhou, S.-N. Zhu, M. Lem, A. Keightley, B. M. Steer, A. C. Schuh, S. L. Adamson, et al. Endothelial Nitric Oxide Synthase Gene Expression During Murine Embryogenesis: Commencement of Expression in the Embryo Occurs With the Establishment of a Unidirectional Circulatory System Circ. Res., July 3, 2008; 103(1): 24 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Borer and L. N. Girardi Repair of the congenitally bicuspid regurgitant aortic valve a strategic advance. J. Am. Coll. Cardiol., July 1, 2008; 52(1): 50 - 51. [Full Text] [PDF]
|
|
|
|
|
|
Y. Bosse, P. Mathieu, and P. Pibarot Genomics: The Next Step to Elucidate the Etiology of Calcific Aortic Valve Stenosis J. Am. Coll. Cardiol., April 8, 2008; 51(14): 1327 - 1336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. B. Donnelly Cardiac Valvular Pathology: Comparative Pathology and Animal Models of Acquired Cardiac Valvular Diseases Toxicol Pathol, February 1, 2008; 36(2): 204 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. C. W. Groenendijk, K. Van der Heiden, B. P. Hierck, and R. E. Poelmann The Role of Shear Stress on ET-1, KLF2, and NOS-3 Expression in the Developing Cardiovascular System of Chicken Embryos in a Venous Ligation Model Physiology, December 1, 2007; 22(6): 380 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M C Pustovrh, A Jawerbaum, V White, E Capobianco, R Higa, N Martinez, J J Lopez-Costa, and E Gonzalez The role of nitric oxide on matrix metalloproteinase 2 (MMP2) and MMP9 in placenta and fetus from diabetic rats Reproduction, October 1, 2007; 134(4): 605 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Sierro, C. Biben, L. Martinez-Munoz, M. Mellado, R. M. Ransohoff, M. Li, B. Woehl, H. Leung, J. Groom, M. Batten, et al. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7 PNAS, September 11, 2007; 104(37): 14759 - 14764. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Matt, A. von Orelli, F. Bernet, T. Grussenmeyer, I. Lefkovits, and H.-R. Zerkowski Proteomics of Ascending Aortic Aneurysm with Bicuspid or Tricuspid Aortic Valve Asian Cardiovasc Thorac Ann, June 1, 2007; 15(3): 185 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Aicher, C. Urbich, A. Zeiher, S. Dimmeler, and H.-J. Schafers Endothelial Nitric Oxide Synthase in Bicuspid Aortic Valve Disease Ann. Thorac. Surg., April 1, 2007; 83(4): 1290 - 1294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lepic, D. Burger, X. Lu, W. Song, and Q. Feng Lack of endothelial nitric oxide synthase decreases cardiomyocyte proliferation and delays cardiac maturation Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1240 - C1246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Aboulhosn and J. S. Child Left Ventricular Outflow Obstruction: Subaortic Stenosis, Bicuspid Aortic Valve, Supravalvar Aortic Stenosis, and Coarctation of the Aorta Circulation, November 28, 2006; 114(22): 2412 - 2422. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Majumdar, M. Yagubyan, G. Sarkar, M. E. Bolander, and T. M. Sundt III Bicuspid aortic valve and ascending aortic aneurysm are not associated with germline or somatic homeobox NKX2-5 gene polymorphism in 19 patients J. Thorac. Cardiovasc. Surg., June 1, 2006; 131(6): 1301 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Warnes The Adult With Congenital Heart Disease: Born To Be Bad? J. Am. Coll. Cardiol., July 5, 2005; 46(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C.W. Groenendijk, B. P. Hierck, J. Vrolijk, M. Baiker, M. J.B.M. Pourquie, A. C. Gittenberger-de Groot, and R. E. Poelmann Changes in Shear Stress-Related Gene Expression After Experimentally Altered Venous Return in the Chicken Embryo Circ. Res., June 24, 2005; 96(12): 1291 - 1298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Verma, P. E. Szmitko, P. W. M. Fedak, L. Errett, D. A. Latter, and T. E. David Can statin therapy alter the natural history of bicuspid aortic valves? Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2547 - H2549. [Full Text] [PDF]
|
|
|
|
|
|
S. Kanno, P. K. M. Kim, K. Sallam, J. Lei, T. R. Billiar, and L. L. Shears II Nitric oxide facilitates cardiomyogenesis in mouse embryonic stem cells PNAS, August 17, 2004; 101(33): 12277 - 12281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Q. Zhou, F. S. Foster, B. J. Nieman, L. Davidson, X. J. Chen, and R. M. Henkelman Comprehensive transthoracic cardiac imaging in mice using ultrasound biomicroscopy with anatomical confirmation by magnetic resonance imaging Physiol Genomics, July 8, 2004; 18(2): 232 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N.N. Han, S. Babaei, M. Robb, T. Lee, R. Ridsdale, C. Ackerley, M. Post, and D. J. Stewart Defective Lung Vascular Development and Fatal Respiratory Distress in Endothelial NO Synthase-Deficient Mice: A Model of Alveolar Capillary Dysplasia? Circ. Res., April 30, 2004; 94(8): 1115 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Macatee, B. P. Hammond, B. R. Arenkiel, L. Francis, D. U. Frank, and A. M. Moon Ablation of specific expression domains reveals discrete functions of ectoderm- and endoderm-derived FGF8 during cardiovascular and pharyngeal development Development, December 22, 2003; 130(25): 6361 - 6374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C A Warnes Bicuspid aortic valve and coarctation: two villains part of a diffuse problem Heart, September 1, 2003; 89(9): 965 - 966. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Babaei, K. Teichert-Kuliszewska, Q. Zhang, N. Jones, D. J. Dumont, and D. J. Stewart Angiogenic Actions of Angiopoietin-1 Require Endothelium-Derived Nitric Oxide Am. J. Pathol., June 1, 2003; 162(6): 1927 - 1936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ou, Z. Ou, D. G. McCarver, R. N. Hines, K. T. Oldham, A. W. Ackerman, and K. A. Pritchard Jr. Trichloroethylene Decreases Heat Shock Protein 90 Interactions with Endothelial Nitric Oxide Synthase: Implications for Endothelial Cell Proliferation Toxicol. Sci., May 1, 2003; 73(1): 90 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. T. Nkomo, M. Enriquez-Sarano, N. M. Ammash, L. J. Melton III, K. R. Bailey, V. Desjardins, R. A. Horn, and A. J. Tajik Bicuspid Aortic Valve Associated With Aortic Dilatation: A Community-Based Study Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 351 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhao, X. Lu, and Q. Feng Deficiency in endothelial nitric oxide synthase impairs myocardial angiogenesis Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2371 - H2378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W.M. Fedak, S. Verma, T. E. David, R. L. Leask, R. D. Weisel, and J. Butany Clinical and Pathophysiological Implications of a Bicuspid Aortic Valve Circulation, August 20, 2002; 106(8): 900 - 904. [Full Text] [PDF]
|
|
|
|
|
|
Q. Feng, W. Song, X. Lu, J. A. Hamilton, M. Lei, T. Peng, and S.-P. Yee Development of Heart Failure and Congenital Septal Defects in Mice Lacking Endothelial Nitric Oxide Synthase Circulation, August 13, 2002; 106(7): 873 - 879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. M. Fedak, S. Verma, J. Butany, R. D. Weisel, and T. E. David Aortic valve malformations and pulmonary autograft root dilatation J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1222 - 1223. [Full Text] [PDF]
|
|
|
|
 |
|
 B. C Kone Molecular biology of natriuretic peptides and nitric oxide synthases Cardiovasc Res, August 15, 2001; 51(3): 429 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Shi, X. Wang, D. M. Shih, V. E. Laubach, M. Navab, and A. J. Lusis Paradoxical Reduction of Fatty Streak Formation in Mice Lacking Endothelial Nitric Oxide Synthase Circulation, April 30, 2002; 105(17): 2078 - 2082. [Abstract] [Full Text] [PDF]
|
|