Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Zonula occludens-1 ZO-1 is involved in the regulation of cell-cell junctions between endothelial cells ECs.
YB-1 expression is essential for SG formation and for the cytoprotective effects induced by ZO-1 downregulation. In the developing retinal vascular plexus of newborn mice, ECs at the front of growing vessels express less ZO-1 but display more YBpositive granules than ECs located in the vascular plexus.
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Endothelial-specific deletion of ZO-1 in mice at post-natal day 7 markedly increased the presence of YBpositive granules in ECs of retinal blood vessels, altered tip EC morphology and vascular patterning, resulting in aberrant endothelial proliferation, and arrest in the expansion of the retinal vasculature. Cell-cell junctions between endothelial cells ECs are constantly remodeled during the formation of new blood vessels 1 , 2.
Intercellular junctions between ECs are generally formed by homotypic interactions between transmembrane proteins connected to a network of intracellular cytosolic proteins that integrate signaling events essential for angiogenesis 3. In particular, ZO-1 deficiency in mice leads to defective angiogenesis in the yolk sac, although EC differentiation appears to be normal 6. ZO-1 functions as a major cytoskeletal organizer in ECs as it orchestrates adherens junctions to control barrier function, cell migration, and angiogenesis 7 , 8.
It has been previously reported that vascular endothelial growth factor VEGF induces phosphorylation of both ZO-1 and the plasma membrane protein occludin, resulting in the disruption of the localization of ZO-1 at cell junctions and increased permeability of EC monolayers 9 , Furthermore, we previously identified ZO-1 as being at the center of a signaling nexus essential for the VEGF-induced proliferation of ECs during angiogenesis Angiogenesis requires the coordination of differentiation, proliferation, polarization, migration, junction rearrangements, and morphological changes of ECs to ensure the growth and integrity of the vascular network 12 , In the context of angiogenic sprouting, as observed during vascular development of the mouse retina, ECs differentiate into tip and stalk cells, a process regulated by Notch-Dll4-VEGF pathways 14 , The highly motile tip cells extend filopodia and branch out in a directional manner from existing vessels, whereas the stalk cells remain behind, maintaining cell-cell contacts during sprouting to preserve vessel integrity and establish lumens for blood perfusion During this collective cell migration process, tip cells at the front have to adopt a polarized morphology while cell-cell junctions at the back of endothelial sprouts should be maintained They interact with each other through the binding of their corresponding PDZ-2 domains 19 , In addition to its roles at cell junctions, ZO-1 is involved in transcriptional modulation through its association with the Y-box binding protein 3 YB-3; aka ZOassociated nucleic acid-binding protein, ZONAB to influence cell proliferation 25 , 26 , Once released from ZO-1, YB-3 can accumulate in the nucleus, where it associates with cell division kinase CDK 4 and promotes cell proliferation ECs are exposed to numerous stresses emanating from their environment; these include reactive oxygen species ROS , oxidized low-density lipoprotein LDL , hypoxic conditions, and turbulent blood flow.
