Submitted to: Circulation Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/5/2003
Publication Date: 9/1/2003
Citation: Hirschi, K.K., Burt, J.M., Hirschi, K.D., Dai, C. 2003. Gap junction communication mediates transforming growth factor-beta activation and endothelial-induced mural cell differentiation. Circulation Research. 93(5):429-437. Interpretive Summary: In order to form functional blood vessels, endothelial cells and smooth muscle cells need to communicate and coordinate their activities. Our study examined intercellular communication in genetically specific mouse embryos, using intracellular dye injection and voltage measurements. We found that gap junction communication between endothelial and smooth muscle gap junctions are required for the activation of a growth factor and subsequent cell differentiation and growth. This finding extends our understanding of the mechanisms of blood vessel generation.
Technical Abstract: During blood vessel assembly, endothelial cells recruit mesenchymal progenitors and induce their differentiation into mural cells via contact-dependent transforming growth factor-beta (TGF-beta) activation. We investigated whether gap junction channels are formed between endothelial cells and recruited mesenchymal progenitors and whether intercellular communication is necessary for endothelial-induced mural cell differentiation. Mesenchymal progenitors from Cx43-/- murine embryos and Cx43+/+ littermates were cocultured with prelabeled endothelial cells. Intracellular dye injection and dual whole-cell voltage clamp revealed that endothelial cells formed gap junction channels with Cx43+/+ but not Cx43-/- progenitors. In coculture with endothelial cells, Cx43-/- progenitors did not undergo mural cell differentiation as did Cx43+/+ cells. Stable reexpression of Cx43 in Cx43-/- cells (reCx43) restored their ability to form gap junctions with endothelial cells and undergo endothelial-induced mural cell differentiation. Cocultures of endothelial cells and either Cx43+/+ or reCx43 mesenchymal cells produced activated TGF-beta; endothelial-Cx43-/- cocultures did not. However, Cx43-/- cells did produce latent TGF-beta and undergo mural cell differentiation in response to exogenous TGF-beta1. These studies indicate that gap junction communication between endothelial and mesenchymal cells mediates TGF-beta activation and subsequent mural cell differentiation