on May 4, 2006
Published online before print May 4, 2006, doi: 10.1161/01.ATV.0000225287.20034.2c
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Submitted on January 3, 2006
Accepted on April 24, 2006
Transforming Growth Factor-
s and Vascular Disorders
Alex Bobik *
From the Cell Biology Laboratory, Baker Heart Research Institute, Melbourne, Australia.
* To whom correspondence should be addressed. E-mail: alex.bobik{at}baker.edu.au.
Abstract--Transforming growth factor-
(TGF-) superfamily members, TGF- and bone morphogenetic proteins (BMPs), are potent regulatory cytokines with diverse functions on vascular cells. They signal through heteromeric type I and II receptor complexes activating Smad-dependent and Smad-independent signals, which regulate proliferation, differentiation, and survival. They are potent regulators of vascular development and vessel remodeling and play key roles in atherosclerosis and restenosis, regulating endothelial, smooth muscle cell, macrophage, T cell, and probably vascular calcifying cell responses. In atherosclerosis, TGF- regulates lesion phenotype by controlling T-cell responses and stimulating smooth muscle cells to produce collagen. It contributes to restenosis by augmenting neointimal cell proliferation and collagen accumulation. Defective TGF- signaling in endothelial cells attributable to mutations in endoglin or the type I receptor ALK-1 leads to hereditary hemorrhagic telangiectasia, whereas defective BMP signaling attributable to mutations in the BMP receptor II has been associated with development of primary pulmonary hypertension. The development of mouse models with either cell type-specific or general inactivation of TGF-/BMP signaling has started to reveal the importance of the regulatory network of TGF-/BMP pathways in vivo and their significance for atherosclerosis, hereditary hemorrhagic telangiectasia, and primary pulmonary hypertension. This review highlights recent findings that have advanced our understanding of the roles of TGF- superfamily members in regulating vascular cell responses and provides likely avenues for future research that may lead to novel pharmacological therapies for the treatment or prevention of vascular disorders.
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