Article ; Online: Rap1 small GTPase is essential for maintaining pulmonary endothelial barrier function in mice.
2024 Volume 37, Issue 12, Page(s) e23310
Abstract: Vascular permeability is dynamically but tightly controlled by vascular endothelial (VE)-cadherin-mediated endothelial cell-cell junctions to maintain homeostasis. Thus, impairments of VE-cadherin-mediated cell adhesions lead to hyperpermeability, ... ...
| Abstract | Vascular permeability is dynamically but tightly controlled by vascular endothelial (VE)-cadherin-mediated endothelial cell-cell junctions to maintain homeostasis. Thus, impairments of VE-cadherin-mediated cell adhesions lead to hyperpermeability, promoting the development and progression of various disease processes. Notably, the lungs are a highly vulnerable organ wherein pulmonary inflammation and infection result in vascular leakage. Herein, we showed that Rap1, a small GTPase, plays an essential role for maintaining pulmonary endothelial barrier function in mice. Endothelial cell-specific Rap1a/Rap1b double knockout mice exhibited severe pulmonary edema. They also showed vascular leakage in the hearts, but not in the brains. En face analyses of the pulmonary arteries and 3D-immunofluorescence analyses of the lungs revealed that Rap1 potentiates VE-cadherin-mediated endothelial cell-cell junctions through dynamic actin cytoskeleton reorganization. Rap1 inhibits formation of cytoplasmic actin bundles perpendicularly binding VE-cadherin adhesions through inhibition of a Rho-ROCK pathway-induced activation of cytoplasmic nonmuscle myosin II (NM-II). Simultaneously, Rap1 induces junctional NM-II activation to create circumferential actin bundles, which anchor and stabilize VE-cadherin at cell-cell junctions. We also showed that the mice carrying only one allele of either Rap1a or Rap1b out of the two Rap1 genes are more vulnerable to lipopolysaccharide (LPS)-induced pulmonary vascular leakage than wild-type mice, while activation of Rap1 by administration of 007, an activator for Epac, attenuates LPS-induced increase in pulmonary endothelial permeability in wild-type mice. Thus, we demonstrate that Rap1 plays an essential role for maintaining pulmonary endothelial barrier functions under physiological conditions and provides protection against inflammation-induced pulmonary vascular leakage. |
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| MeSH term(s) | Animals ; Mice ; Actins/metabolism ; Cadherins/metabolism ; Capillary Permeability ; Cell Adhesion/physiology ; Endothelium, Vascular/metabolism ; Lipopolysaccharides/metabolism ; Lung/metabolism ; rap1 GTP-Binding Proteins/genetics ; rap1 GTP-Binding Proteins/metabolism |
| Chemical Substances | Actins ; Cadherins ; Lipopolysaccharides ; rap1 GTP-Binding Proteins (EC 3.6.5.2) ; rap1A protein, mouse ; Rap1b protein, mouse (EC 3.6.1.-) |
| Language | English |
| Publishing date | 2024-01-01 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 639186-2 |
| ISSN | 1530-6860 ; 0892-6638 |
| ISSN (online) | 1530-6860 |
| ISSN | 0892-6638 |
| DOI | 10.1096/fj.202300830RR |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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