Abstract
How individual components of the vascular basement membrane influence endothelial cell behaviour remains unclear. Here we show that laminin α4 (Lama4) regulates tip cell numbers and vascular density by inducing endothelial Dll4/Notch signalling in vivo. Lama4 deficiency leads to reduced Dll4 expression, excessive filopodia and tip cell formation in the mouse retina, phenocopying the effects of Dll4/Notch inhibition. Lama4-mediated Dll4 expression requires a combination of integrins in vitro and integrin β1 in vivo. We conclude that appropriate laminin/integrin-induced signalling is necessary to induce physiologically functional levels of Dll4 expression and regulate branching frequency during sprouting angiogenesis in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Basement Membrane / metabolism*
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Basement Membrane / ultrastructure
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Calcium-Binding Proteins
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Human Umbilical Vein Endothelial Cells / cytology*
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Human Umbilical Vein Endothelial Cells / metabolism*
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Human Umbilical Vein Endothelial Cells / ultrastructure
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Humans
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Integrins / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism*
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Laminin / deficiency
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Laminin / metabolism
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Membrane Proteins / metabolism*
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Mice
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Neovascularization, Physiologic
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Receptors, Notch / antagonists & inhibitors
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Receptors, Notch / metabolism*
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Signal Transduction*
Substances
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Adaptor Proteins, Signal Transducing
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Calcium-Binding Proteins
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DLL4 protein, mouse
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Integrins
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Intracellular Signaling Peptides and Proteins
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Lama4 protein, mouse
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Laminin
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Membrane Proteins
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Receptors, Notch