Distinct regulation of gene expression in human endothelial cells by TGF-beta and its receptors.

Transforming growth factor beta (TGF-beta) and its signaling mediators play essential roles in angiogenesis-formation of new blood vessels, as evidenced by targeted gene disruption in mice and their mutations in human vascular dysplasia. However, little is known about the molecular basis of TGF-beta function in vascular formation. To study the function of TGF-beta signaling in angiogenesis and to elucidate the signaling specificity of TGF-beta receptors at the gene transcriptional level, we analyzed the expression profile of the genes regulated by TGF-beta and its type I receptors ALK1 and ALK5 in human microvessel endothelial cells (ECs). Global change of gene expression profiles was examined by microarray and RT-PCR analyses in the ECs treated with TGF-beta1 or by adenoviral expression of the active ALK1 or ALK5. We found that the profiles of the genes regulated by TGF-beta, ALK1 and ALK5 are distinct from each other, although some of genes are modulated by all of them. TGF-beta regulated far more genes than ALK1 and ALK5 did. ALK1 enhanced the formation of tube-like structures of ECs, while ALK5 stimulates EC aggregation. Our results suggest that ALK1 appears to have important functions in regulating proliferation of ECs, whereas ALK5 tends to modulate cell-cell interaction and cell adhesion and extracellular matrix remodeling.