Abstract
Lymphangiogenesis is a highly regulated process that involves the reprogramming of venous endothelial cells into early lymphatic endothelial cells. This reprogramming not only displays a polarized expression pattern from the cardinal vein, but also demonstrates vascular specificity; early lymphatics only develop from the cardinal vein and not the related dorsal aorta. In our transgenic model of lymphangiogenesis, we demonstrate that Prox1 overexpression has the ability to reprogram venous endothelium but not early arterial endothelial cells in vivo, in spite of the fact that Prox1 expression is forced onto both vascular beds. Our observations suggest that this specificity during embryogenesis may be due to cell-cell interactions between the developing arterial endothelial cells and smooth muscle cells. These conclusions have far reaching implications on how we understand the vascular specificity of lymphangiogenesis.
Highlights
Subsequent to vasculogenesis, endothelial cells specialize into arterial and venous cell types through a complex mechanism that starts with a number of key signaling molecules
Perturbation of the Notch receptor or its ligand Dll4 inhibits the development of an arterial cell fate from the venous endothelium, characterized by the downregulation of artery-specific markers such as EphrinB2 and Notch5
Double transgenic embryos suffer from edema The early development of the lymphatic vasculature depends on the regulated expression of Prox1 on the cardinal vein
Summary
Subsequent to vasculogenesis, endothelial cells specialize into arterial and venous cell types through a complex mechanism that starts with a number of key signaling molecules. The Notch receptor system is one of the pathways that have been implicated to play a critical role in the determination of arterial cell fate [1,2,3]. Perturbation of the Notch receptor or its ligand Dll inhibits the development of an arterial cell fate from the venous endothelium, characterized by the downregulation of artery-specific markers such as EphrinB2 and Notch. Venous markers are upregulated such as EphB4 [1]. The fate of the venous endothelium appears to have a determined molecular program. The transcription factor COUP-TFII has been found to repress the arterial phenotype; deletion of COUPTFII results in the upregulation of NP-1 and Notch resulting in the arterialization of venous endothelium [4]
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