The Wnt/β-Catenin Pathway Modulates Vascular Remodeling and Specification by Upregulating Dll4/Notch Signaling
The Wnt/β-Catenin Pathway Modulates Vascular Remodeling and Specification by Upregulating Dll4/Notch Signaling
The Wnt/beta-catenin pathway is evolutionary conserved signaling system that regulates cell differentiation and organogenesis. We show that endothelial specific stabilization of Wnt/beta-catenin signaling alters early vascular development in the embryo. The phenotype resembles that induced by upregulation of Notch signaling, including lack of vascular remodeling, altered elongation of the intersomitic vessels, defects in branching, and loss of venous identity. Both in vivo and in vitro data show that beta-catenin upregulates Dll4 transcription and strongly increases Notch signaling in the endothelium, leading to functional and morphological alterations. The functional consequences of beta-catenin signaling depend on the stage of vascular development and are lost when a gain-of-function mutation is induced at a late stage of development or postnatally. Our findings establish a link between Wnt and Notch signaling in vascular development. We propose that early and sustained beta-catenin signaling prevents correct endothelial cell differentiation, altering vascular remodeling and arteriovenous specification.
- University of Milan Italy
- University of Milan Italy
- University of California, Los Angeles United States
- University of Münster Germany
- UCLA United States
Mice, Knockout, Transcriptional Activation, Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, Endothelial Cells, Gene Expression Regulation, Developmental, Membrane Proteins, Neovascularization, Physiologic, DEVBIO, Cell Differentiation, Mice, Transgenic, Arteries, Mice, Inbred C57BL, Mice, Animals, Humans, Receptor, Notch1, Cells, Cultured, Developmental Biology, Adaptor Proteins, Signal Transducing, Cell Proliferation, Signal Transduction
Mice, Knockout, Transcriptional Activation, Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, Endothelial Cells, Gene Expression Regulation, Developmental, Membrane Proteins, Neovascularization, Physiologic, DEVBIO, Cell Differentiation, Mice, Transgenic, Arteries, Mice, Inbred C57BL, Mice, Animals, Humans, Receptor, Notch1, Cells, Cultured, Developmental Biology, Adaptor Proteins, Signal Transducing, Cell Proliferation, Signal Transduction
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