Published online before print August 14, 2003, doi: 10.1161/01.RES.0000091259.84556.D5
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Submitted on November 2, 2002
Revised on August 5, 2003
Accepted on August 5, 2003
Gap Junction Communication Mediates Transforming Growth Factor-
Activation and Endothelial-Induced Mural Cell Differentiation
Karen K. Hirschi *;
From the Departments of Pediatrics (K.K.H., K.D.H., C.D.), Molecular and Cellular Biology (K.K.H.), and Molecular and Human Genetics (K.D.H.), Children's Nutrition Research Center (K.K.H, K.D.H., C.D.), and Center for Cell and Gene Therapy (K.K.H., C.D.), Baylor College of Medicine, Houston, Tex; Department of Physiology (J.M.B.), University of Arizona, College of Medicine, Tucson, Ariz.
* To whom correspondence should be addressed. E-mail: khirschi{at}bcm.tmc.edu.
During blood vessel assembly, endothelial cells recruit mesenchymal progenitors and induce their differentiation into mural cells via contact-dependent transforming growth factor-
(TGF-) 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-; endothelial-Cx43-/- cocultures did not. However, Cx43-/- cells did produce latent TGF- and undergo mural cell differentiation in response to exogenous TGF-1. These studies indicate that gap junction communication between endothelial and mesenchymal cells mediates TGF- activation and subsequent mural cell differentiation.
Key words: blood vessel formation • gap junctions • endothelial cells • smooth muscle differentiation • transforming growth factor-
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