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VASCULAR BIOLOGY

Role of TGF-1 and JNK signaling in capillary tube patterning

Angiogenesis Research Center, Department of Medicine, Dartmouth-Hitchcock Medical Center, Dartmouth College, Lebanon, New Hampshire 03756

Submitted 19 February 2004 ; accepted in final form 11 June 2004

The transforming growth factor (TGF) family of secretory polypeptides comprises signaling proteins involved in numerous physiological processes, including vascular development and vessel wall integrity. Both pro- and anti-angiogenic effects of TGF-1 have also been documented. To study the intracellular mechanisms involved in capillary tube morphogenesis, endothelial cell aggregates were cultured in a fibrin matrix. It was found that the pattern of capillary tubes formed in a fibrin matrix was altered in response to TGF-1 treatment such that the capillary-like structures displayed a bipolarized pattern. In contrast, in untreated control and fibroblast growth factor-2-treated cells, the pattern of capillary tubes formed was random. TGF-1 also downregulated urokinase-type plasminogen activator (uPA) activity while upregulating PA inhibitor (PAI)-1 and thrombospondin (TSP)1 gene expression. To investigate the signaling cascade mediating the phenotypic changes observed, pharmacological inhibitors of p38 MAPK, Sp1 transcription factor, c-Jun NH₂-terminal kinase (JNK), and the cytokine TNF- were used. The p38 MAPK inhibitor SB203580 reversed the TGF-1-dependent inhibition of uPA activity but not its morphogenetic effect. In contrast, the DNA intercalator WP631 and TNF- counteracted the TGF-1-induced morphogenetic effect while the JNK inhibitor SP600125 effectively inhibited capillary tube formation. These results indicate that the TGF-1-induced capillary tube pattern is independent of the p38 MAPK-activated PAI-1 and TSP1 expression, but the mechanism involves Sp1-dependent transcriptional regulation. The results also raise the possibility that the JNK pathway, which controls convergent extension in Xenopus, may be involved in vessel wall patterning in mammalian systems.

metalloproteinase; plasminogen activator; p38 MAPK; thrombospondin 1; Sp1

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