This Article Full Text Full Text (PDF) All Versions of this Article: 24/3/405    most recent 01.ATV.0000109171.50229.33v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed 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 Tai, S. C. Articles by Marsden, P. A. Search for Related Content PubMed PubMed Citation Articles by Tai, S. C. Articles by Marsden, P. A. Related Collections Pathophysiology Gene expression Gene regulation Genetically altered mice Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:405.)
© 2004 American Heart Association, Inc.

Brief Reviews

Endothelial Nitric Oxide Synthase

A New Paradigm for Gene Regulation in the Injured Blood Vessel

Sharon C. Tai; G. Brett Robb; Philip A. Marsden

From the Renal Division and Department of Medicine, St. Michael’s Hospital and University of Toronto, Ontario, Canada.

Correspondence to Philip A. Marsden, Room 7358, Medical Sciences Building, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S 1A8 Canada. E-mail p.marsden{at}utoronto.ca

Advances in our understanding of the molecular mechanisms involved in the constitutive and regulated expression of endothelial nitric oxide synthase (eNOS) mRNA expression present a new level of complexity to the study of endothelial gene regulation in health and disease. Recent studies highlight the contribution of both transcription and RNA stability to net steady-state mRNA levels of eNOS in vascular endothelium, introducing a new paradigm to gene regulation in the injured blood vessel. Constitutive eNOS expression is dependent on basal transcription machinery in the core promoter, involving positive and negative protein–protein and protein–DNA interactions. Chromatin-based mechanisms and epigenetic events also regulate expression of eNOS at the transcriptional level in a cell-restricted fashion. Although constitutively active, important physiological and pathophysiologic stimuli alter eNOS gene transcription rates. For instance, eNOS transcription rates increase in response to lysophosphatidylcholine, shear stress, and TGF-ß, among others. Under basal conditions, eNOS mRNA is extremely stable. Surprisingly, posttranscriptional mechanisms have emerged as important regulatory pathways in the observed decreases in eNOS expression in some settings. In models of inflammation, proliferation/injury, oxidized low-density lipoprotein treatment, and hypoxia, eNOS mRNA destabilization plays a significant role in the rapid downregulation of eNOS mRNA levels.

Key Words: atherosclerosis • endothelium • gene regulation • mRNA stability • transcription

This article has been cited by other articles:

				N. Sawada, S. Salomone, H.-H. Kim, D. J. Kwiatkowski, and J. K. Liao Regulation of Endothelial Nitric Oxide Synthase and Postnatal Angiogenesis by Rac1 Circ. Res., August 15, 2008; 103(4): 360 - 368. [Abstract] [Full Text] [PDF]

				M. E. Hartnett, D. Martiniuk, G. Byfield, P. Geisen, G. Zeng, and V. L. Bautch Neutralizing VEGF Decreases Tortuosity and Alters Endothelial Cell Division Orientation in Arterioles and Veins in a Rat Model of ROP: Relevance to Plus Disease Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 3107 - 3114. [Abstract] [Full Text] [PDF]

				C. C. Matouk and P. A. Marsden Epigenetic Regulation of Vascular Endothelial Gene Expression Circ. Res., April 25, 2008; 102(8): 873 - 887. [Abstract] [Full Text] [PDF]

				J. Li, A. Wilson, R. Kuruba, Q. Zhang, X. Gao, F. He, L.-M. Zhang, B. R. Pitt, W. Xie, and S. Li FXR-mediated regulation of eNOS expression in vascular endothelial cells Cardiovasc Res, January 1, 2008; 77(1): 169 - 177. [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]

				L. Ostergaard, E. Stankevicius, M. R. Andersen, Y. Eskildsen-Helmond, T. Ledet, M. J. Mulvany, and U. Simonsen Diminished NO release in chronic hypoxic human endothelial cells Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2894 - H2903. [Abstract] [Full Text] [PDF]

				M. P. Coggins and K. D. Bloch Nitric Oxide in the Pulmonary Vasculature Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 1877 - 1885. [Abstract] [Full Text] [PDF]

				J. E. Fish, C. C. Matouk, E. Yeboah, S. C. Bevan, M. Khan, K. Patil, M. Ohh, and P. A. Marsden Hypoxia-inducible Expression of a Natural cis-Antisense Transcript Inhibits Endothelial Nitric-oxide Synthase J. Biol. Chem., May 25, 2007; 282(21): 15652 - 15666. [Abstract] [Full Text] [PDF]

				Y. Suarez, C. Fernandez-Hernando, J. S. Pober, and W. C. Sessa Dicer Dependent MicroRNAs Regulate Gene Expression and Functions in Human Endothelial Cells Circ. Res., April 27, 2007; 100(8): 1164 - 1173. [Abstract] [Full Text] [PDF]

				C. D. Searles Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression Am J Physiol Cell Physiol, November 1, 2006; 291(5): C803 - C816. [Abstract] [Full Text] [PDF]

				M. Saura, C. Zaragoza, C. Bao, B. Herranz, M. Rodriguez-Puyol, and C. J. Lowenstein Stat3 Mediates Interelukin-6 Inhibition of Human Endothelial Nitric-oxide Synthase Expression J. Biol. Chem., October 6, 2006; 281(40): 30057 - 30062. [Abstract] [Full Text] [PDF]

				M. Kelm Significance of Vascular Nitric Oxide Synthase Pathways in Coronary Artery Disease: A Multiple-Level Biomarker Strategy J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1175 - 1176. [Full Text] [PDF]

				K. Noma, N. Oyama, and J. K. Liao Physiological role of ROCKs in the cardiovascular system Am J Physiol Cell Physiol, March 1, 2006; 290(3): C661 - C668. [Abstract] [Full Text] [PDF]

				J. E. Church and D. Fulton Differences in eNOS Activity Because of Subcellular Localization Are Dictated by Phosphorylation State Rather than the Local Calcium Environment J. Biol. Chem., January 20, 2006; 281(3): 1477 - 1488. [Abstract] [Full Text] [PDF]

				H. Ou, Y. H. Shen, B. Utama, J. Wang, X. Wang, J. Coselli, and X. L. Wang Effect of Nuclear Actin on Endothelial Nitric Oxide Synthase Expression Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2509 - 2514. [Abstract] [Full Text] [PDF]

				D. G. Haider, R. A. Bucek, A. G. Giurgea, G. Maurer, H. Glogar, E. Minar, M. Wolzt, M. R. Mehrabi, and M. Baghestanian PGE1 analog alprostadil induces VEGF and eNOS expression in endothelial cells Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2066 - H2072. [Abstract] [Full Text] [PDF]

				J. E. Fish, C. C. Matouk, A. Rachlis, S. Lin, S. C. Tai, C. D'Abreo, and P. A. Marsden The Expression of Endothelial Nitric-oxide Synthase Is Controlled by a Cell-specific Histone Code J. Biol. Chem., July 1, 2005; 280(26): 24824 - 24838. [Abstract] [Full Text] [PDF]

				G. B. Robb, A. R. Carson, S. C. Tai, J. E. Fish, S. Singh, T. Yamada, S. W. Scherer, K. Nakabayashi, and P. A. Marsden Post-transcriptional Regulation of Endothelial Nitric-oxide Synthase by an Overlapping Antisense mRNA Transcript J. Biol. Chem., September 3, 2004; 279(36): 37982 - 37996. [Abstract] [Full Text] [PDF]

				Y. Chan, J. E. Fish, C. D'Abreo, S. Lin, G. B. Robb, A.-M. Teichert, F. Karantzoulis-Fegaras, A. Keightley, B. M. Steer, and P. A. Marsden The Cell-specific Expression of Endothelial Nitric-oxide Synthase: A ROLE FOR DNA METHYLATION J. Biol. Chem., August 13, 2004; 279(33): 35087 - 35100. [Abstract] [Full Text] [PDF]