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Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:679-680
doi: 10.1161/01.ATV.0000209949.86606.c2
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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{at}vanderbilt.edu

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 of Arteriosclerosis, Thrombosis, and Vascular Biology, Otsuka and colleagues explore the effects of TGF-ß1 in promoting intimal growth in uninjured murine carotid arteries.15 As expected, adenoviral delivered TGF-ß1 stimulates PAI-1 expression in transduced arteries, whereas the null adenoviral construct has little effect. Adenoviral-mediated overexpression of TGF-ß1 promotes the accumulation of matrix-rich highly cellular intimal arterial lesions. In contrast, adenoviral TGF-ß1 overexpression has modest effects on the size or the cellularity of the arterial media. Interestingly, the authors found that PAI-1–deficient mice are essentially protected from TGF-ß1–induced intimal expansion, even though PAI-1 deficiency is associated with increased total and active TGF-ß1 secretion after treatment with adenoviral TGF-ß1. These findings correspond quite well with recent work published by Krag et al who reported that PAI-1 gene deficiency attenuates TGF-ß1–induced kidney disease, by decreasing both glomerular and interstitial ECM deposition.16

The authors conclude that PAI-1 is a critical mediator of TGF-ß1–induced intimal growth and a key negative regulator of TGF-ß1 expression in the arterial wall. These conclusions may be accurate but need to be considered in the experimental context with some important reservations. The model of intimal growth used in these studies involved uninjured mouse carotid arteries. The functional interaction between TGF-ß1 and PAI-1 in diseased human vasculature undoubtedly presents a much more complex environment, and this complexity may amplify or nullify the effects reported here. The presence of other cytokines, transcriptional complexes, and cell types in an injured vessel would likely present powerful confounding effects on the relatively simple linear relationship between TGF-ß1 and PAI-1 suggested by this study. In fact, at present, there is no direct evidence that TGF-ß1 regulates vascular PAI-1 production in diseases associated with increased arterial PAI-1, including type 2 diabetes mellitus17 and atherosclerosis. However, this work does indicate that important and undesirable vascular effects of TGF-ß1 are strongly influenced by PAI-1. This in turn adds greater momentum for the development and testing of specific PAI-1 antagonists, which have been reported to reduce the development of arteriosclerosis18 and intravascular thrombosis,19 may provide additional benefits in the treatment of arterial disease that is accelerated or influenced by local effects of TGF-ß1.

In Euclidean geometry, the area of a circle is defined as {pi}xradius2 (A={pi}r2). Based on the findings and interactions reported here, it appears that the biological homonym PAI is a powerful determinant of intimal area in response to TGF-ß1 (A&TGF-ß1xPAI-1). Down


Figure 1
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  		Mechanisms and effects described in the manuscript by Otsuka et al. A, Effects of adenoviral-delivered TGF-ß1 treatment in wild-type (WT) mice. TGF-ß1 induced intimal expansion, characterized by smooth muscle cell (SMC) migration into the area, matrix accumulation (shown in blue), induction of expression of PAI-1, and TGF-ß1 production. In contrast, in PAI-1 deficient mice (B), there was comparatively greater TGF-ß1 production but no evidence of intimal expansion and SMC migration.


*    References
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 *References
 

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  7. Bouchie JL, Hansen H, Feener EP. Natriuretic factors and nitric oxide suppress plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Role of cGMP in the regulation of the plasminogen system. Arterioscler Thromb Vasc Biol. 1998; 18: 1771–1779.[Abstract/Free Full Text]
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Related Article:

Transforming Growth Factor Beta 1 Induces Neointima Formation Through Plasminogen Activator Inhibitor-1–Dependent Pathways
Goro Otsuka, Ramtin Agah, Andrew D. Frutkin, Thomas N. Wight, and David A. Dichek
Arterioscler. Thromb. Vasc. Biol. 2006 26: 737-743. [Abstract] [Full Text] [PDF]



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