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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:679.)
© 2006 American Heart Association, Inc.

Editorials

PAI-1 and TGF-ß

Unmasking the Real Driver of TGF-ß–Induced Vascular Pathology

Douglas E. Vaughan

From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Douglas Vaughan, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn. E-mail vicki.kivett@vanderbilt.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Atherosclerosis is an extremely complex disease process in which genetic, lipid, cellular, and immunologic factors combine to determine the location, severity, and timing of lesion development and clinical events.¹ With the current epidemic of obesity and the metabolic syndrome, additional factors are now recognized as contributors to the vascular disease equation, including plasminogen activator inhibitor-1 (PAI-1),² which is one of the critical physiological regulators of plasminogen activation. PAI-1 accumulates in atherosclerotic lesions³ and contributes to a variety of vascular pathologies including coronary artery thrombosis⁴ and perivascular fibrosis.^5,6 Numerous factors are known to regulate vascular PAI-1 production, including nitric oxide (NO), which directly suppresses PAI-1 expression.⁷ Simply inhibiting vascular NO production stimulates arterial PAI-1 accumulation and promotes the development of PAI-1–dependent perivascular fibrosis.⁸ Other factors promote vascular pathology and arteriosclerosis through mechanisms that likely involve PAI-1, including Angiotensin II⁹ and transforming growth factor-ß1 (TGF-ß1).¹⁰ The important role of TGF-ß in regulating PAI-1 expression has been extensively investigated and, in fact, PAI-1 promoter constructs are widely used in reductionist studies that have defined the molecular mechanisms of TGF-ß–dependent transcriptional activation and suppression.^11–13

See page 737

Although the molecular link between TGF-ß and PAI-1 is well established, the functional impact of this interaction is less well understood. Both TGF-ß1 and TGF-ß3 upregulate PAI-1 expression in vascular tissue at the promoter level. TGF-ß family signaling is positively modulated by various members of the Smad family of signal transduction proteins, and these transcription factors bind to defined elements in the PAI-1 promoter.¹⁴ In this issue . . . [Full Text of this Article]

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				W. P. Fay, N. Garg, and M. Sunkar Vascular Functions of the Plasminogen Activation System Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1231 - 1237. [Abstract] [Full Text] [PDF]