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1.
Vascul Pharmacol ; 112: 8-16, 2019 01.
Article in English | MEDLINE | ID: mdl-30423447

ABSTRACT

Branching morphogenesis is a fascinating process whereby a simple network of biological tubes increases its complexity by adding new branches to existing ones, generating an enlarged structure of interconnected tubes. Branching morphogenesis has been studied extensively in animals and much has been learned about the regulation of branching at the cellular and molecular level. Here, we discuss studies of the Drosophila trachea and of the vertebrate vasculature, which have revealed how new branches are formed and connect (anastomose), leading to the establishment of complex tubular networks. We briefly describe the cell behaviour underlying tracheal and vascular branching. Although similar at many levels, the branching and anastomosis processes characterized thus far show a number of differences in cell behaviour, resulting in somewhat different tube architectures in these two organs. We describe the similarities and the differences and discuss them in the context of their possible developmental significance. We finish by highlighting some old and new data, which suggest that live imaging of the development of capillary beds in adult animals might reveal yet unexplored endothelial behaviour of endothelial cells.


Subject(s)
Blood Vessels/cytology , Drosophila/cytology , Endothelial Cells/cytology , Epithelial Cells/cytology , Neovascularization, Physiologic , Trachea/cytology , Zebrafish/anatomy & histology , Animals , Blood Vessels/metabolism , Cell Communication , Cell Differentiation , Cell Movement , Cell Proliferation , Cell Shape , Drosophila/metabolism , Endothelial Cells/metabolism , Epithelial Cells/metabolism , Mice , Morphogenesis , Phenotype , Signal Transduction , Trachea/metabolism , Zebrafish/metabolism
2.
Nat Commun ; 9(1): 4826, 2018 11 16.
Article in English | MEDLINE | ID: mdl-30446640

ABSTRACT

Angiogenesis is a dynamic process relying on endothelial cell rearrangements within vascular tubes, yet the underlying mechanisms and functional relevance are poorly understood. Here we show that PI3Kα regulates endothelial cell rearrangements using a combination of a PI3Kα-selective inhibitor and endothelial-specific genetic deletion to abrogate PI3Kα activity during vessel development. Quantitative phosphoproteomics together with detailed cell biology analyses in vivo and in vitro reveal that PI3K signalling prevents NUAK1-dependent phosphorylation of the myosin phosphatase targeting-1 (MYPT1) protein, thereby allowing myosin light chain phosphatase (MLCP) activity and ultimately downregulating actomyosin contractility. Decreased PI3K activity enhances actomyosin contractility and impairs junctional remodelling and stabilization. This leads to overstretched endothelial cells that fail to anastomose properly and form aberrant superimposed layers within the vasculature. Our findings define the PI3K/NUAK1/MYPT1/MLCP axis as a critical pathway to regulate actomyosin contractility in endothelial cells, supporting vascular patterning and expansion through the control of cell rearrangement.


Subject(s)
Actomyosin/genetics , Gene Expression Regulation, Developmental , Myosin-Light-Chain Phosphatase/genetics , Neovascularization, Physiologic/genetics , Phosphatidylinositol 3-Kinases/genetics , Protein Kinases/genetics , Repressor Proteins/genetics , Actomyosin/metabolism , Animals , Body Patterning/genetics , Embryo, Mammalian , Embryo, Nonmammalian , Gene Expression Profiling , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Intercellular Junctions/metabolism , Intercellular Junctions/ultrastructure , Lung/blood supply , Lung/cytology , Lung/growth & development , Lung/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myosin-Light-Chain Phosphatase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein Kinases/metabolism , Repressor Proteins/metabolism , Retina/cytology , Retina/growth & development , Retina/metabolism , Signal Transduction , Zebrafish
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