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      TGF-β 1, -β 2 and -β 3 Cooperate to Facilitate Tubulogenesis in the Explanted Quail Heart

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          Background: Transforming growth factor-β (TGF-β) isoforms have been implicated as both pro- and anti-angiogenic modulators. In this study we addressed the roles of TGF-β isoforms on coronary tubulogenesis. Methods: Embryonic (E6) quail ventricular specimens were explanted onto collagen gels allowing endothelial cells to migrate and form vascular tubes. Growth factors and/or neutralizing growth factor antibodies were added to the cultures. Endothelial cells were identified using a quail endothelial cell marker, QH1. Image analysis was used to quantify aggregate tube length. Results: Addition of any isoform (TGF-β<sub>1</sub>, TGF-β<sub>2</sub> or TGF-β<sub>3</sub>) virtually prevented tubulogenesis (>95% inhibition), while stimulation of tubulogenesis occurred by adding neutralizing antibodies to TGF-β<sub>3</sub>, but not to TGF-β<sub>1</sub> or -β<sub>2</sub>. When all three isoforms were added, tubulogenesis was enhanced, indicating the key role of TGF-β<sub>3</sub>. Documentation of the inhibitory effect of TGF-β isoforms on tubulogenesis is further supported by our experiments in which the marked enhancement of tube formation by bFGF and VEGF was negated when exogenous TGF-β<sub>1</sub>, -β<sub>2</sub>, or -β<sub>3</sub> were added to the cultures. Conclusions: (1) TGF-β<sub>1</sub>, -β<sub>2</sub> and -β<sub>3</sub> each inhibits angiogenesis; (2) cooperation between the three TGF-β isoforms and other angiogenic factors is essential for the regulation of normal tubulogenesis and (3) the stimulatory effect of VEGF or bFGF on tubulogenesis is negated by exogenous TGB-βs.

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          Most cited references 26

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          Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling.

          TGF-beta signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins. The activated TGF-beta receptor induces phosphorylation of two such proteins, Smad2 and Smad3, which form hetero-oligomeric complex(es) with Smad4/DPC4 that translocate to the nucleus, where they then regulate transcriptional responses. However, the mechanisms by which the intracellular signals of TGF-beta are switched off are unclear. Here we report the identification of Smad7, which is related to Smad6. Transfection of Smad7 blocks responses mediated by TGF-beta in mammalian cells, and injection of Smad7 RNA into Xenopus embryos blocks activin/TGF-beta signalling. Smad7 associates stably with the TGF-beta receptor complex, but is not phosphorylated upon TGF-beta stimulation. TGFbeta-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating that the antagonistic effect of Smad7 is exerted at this important regulatory step. TGF-beta rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGF-beta responses.
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            Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction.

            A broad spectrum of biological activities has been proposed for transforming growth factor-beta 3 (TGF-beta 3). To study TGF-beta 3 function in development, TGF-beta 3 null mutant mice were generated by gene-targeting. Within 20 hours of birth, homozygous TGF-beta 3-/- mice die with unique and consistent phenotypic features including delayed pulmonary development and defective palatogenesis. Unlike other null mutants with cleft palate, TGF-beta 3-/- mice lack other concomitant craniofacial abnormalities. This study demonstrates an essential function for TGF-beta 3 in the normal morphogenesis of palate and lung, and directly implicates this cytokine in mechanisms of epithelial-mesenchymal interaction.
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              Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.


                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2004
                03 December 2004
                : 41
                : 6
                : 491-498
                aDepartment of Anatomy and Cell Biology and Cardiovascular Center, University of Iowa, Iowa City, Iowa, and bDepartment of Cell Biology and Anatomy, University of Arizona, Tucson, Ariz., USA
                81805 J Vasc Res 2004;41:491–498
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 8, References: 43, Pages: 8
                Research Paper


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