Select rab GTPases regulate the pulmonary endothelium via endosomal trafficking of vascular endothelial-cadherin

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • Brown University

Details

Original languageEnglish (US)
Pages (from-to)769-781
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Volume54
Issue number6
StatusPublished - Jun 2016
Peer-reviewedYes

Abstract

Pulmonary edema occurs in settings of acute lung injury, in diseases, such as pneumonia, and in acute respiratory distress syndrome. The lung interendothelial junctions are maintained in part by vascular endothelial (VE)-cadherin, an adherens junction protein, and its surface expressionis regulated by endocytic trafficking. TheRab family of small GTPases are regulators of endocytic trafficking. The key trafficking pathways are regulated by Rab4, -7, and -9. Rab4 regulates the recycling of endosomes to the cell surface througha rapidshuttle process, whereas Rab7 and -9 regulate trafficking to the late endosome/lysosome for degradation or from the trans-Golgi network to the late endosome, respectively.We recently demonstrated a role for the endosomal adaptor protein, p18, in regulation of the pulmonary endothelium through enhanced recycling of VE-cadherin to adherens junction. Thus, we hypothesized that Rab4, -7, and -9 regulate pulmonary endothelial barrier function through modulating trafficking of VE-cadherin-positive endosomes. We used Rab mutants with varying activities and associations to the endosome to study endothelial barrier function in vitro and in vivo. Our study demonstrates a key role for Rab4 activation and Rab9 inhibition in regulation of vascular permeability through enhanced VE-cadherin expression at the interendothelial junction. We further showed that endothelial barrier function mediated through Rab4 is dependent on extracellular signal-regulated kinase phosphorylation and activity. Thus, we demonstrate that Rab4 and -9 regulate VE-cadherin levels at the cell surface to modulate the pulmonary endothelium through extracellular signal-regulated kinase-dependent and -independent pathways, respectively. We propose that regulating select Rab GTPases represents novel therapeutic strategies for patients suffering with acute respiratory distress syndrome.

    Research areas

  • Acute respiratory distress syndrome, Endocytosis, Endothelium, Rab GTPase, Vascular endothelial-cadherin

Citation formats

APA

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Chichger, H, Braza, J, Duong, H, Boni, G & Harrington, EO 2016, 'Select rab GTPases regulate the pulmonary endothelium via endosomal trafficking of vascular endothelial-cadherin', American journal of respiratory cell and molecular biology, vol. 54, no. 6, pp. 769-781. https://doi.org/10.1165/rcmb.2015-0286OC