Rap1 small GTPase is essential for maintaining pulmonary endothelial barrier function in mice.

Autor: Yamamoto K; Department of Molecular Pathophysiology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan.; Department of Pharmaceutical Information Science, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.; Laboratory of Vascular and Cellular Dynamics, Department of Medical Sciences, University of Miyazaki, Miyazaki, Japan., Watanabe-Takano H; Department of Molecular Pathophysiology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan., Oguri-Nakamura E; Department of Molecular Pathophysiology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan., Matsuno H; Department of Molecular Pathophysiology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan., Horikami D; Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan., Ishii T; Department of Molecular Pathophysiology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan., Ohashi R; Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan., Kubota Y; Department of Anatomy, Keio University School of Medicine, Tokyo, Japan., Nishiyama K; Laboratory of Vascular and Cellular Dynamics, Department of Medical Sciences, University of Miyazaki, Miyazaki, Japan., Murata T; Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan., Mochizuki N; Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan., Fukuhara S; Department of Molecular Pathophysiology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2023 Dec; Vol. 37 (12), pp. e23310.
DOI: 10.1096/fj.202300830RR
Abstrakt: 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.
(© 2023 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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