title: Control of vascular permeability by atrial natriuretic peptide via a GEF-H1-dependent mechanism.
abstract: Microtubule (MT) dynamics is involved in a variety of cell functions, including control of the endothelial cell (EC) barrier. Release of Rho-specific nucleotide exchange factor GEF-H1 from microtubules activates the Rho pathway of EC permeability. In turn, pathologic vascular leak can be prevented by treatment with atrial natriuretic peptide (ANP). This study investigated a novel mechanism of vascular barrier protection by ANP via modulation of GEF-H1 function. In pulmonary ECs, ANP suppressed thrombin-induced disassembly of peripheral MT and attenuated Rho signaling and cell retraction. ANP effects were mediated by the Rac1 GTPase effector PAK1. Activation of Rac1-PAK1 promoted PAK1 interaction with the Rho activator GEF-H1, inducing phosphorylation of total and MT-bound GEF-H1 and leading to attenuation of Rho-dependent actin remodeling. In vivo, ANP attenuated lung injury caused by excessive mechanical ventilation and TRAP peptide (TRAP/HTV), which was further exacerbated in ANP(-/-) mice. The protective effects of ANP against TRAP/HTV-induced lung injury were linked to the increased pool of stabilized MT and inactivation of Rho signaling via ANP-induced, PAK1-dependent inhibitory phosphorylation of GEF-H1. This study demonstrates a novel protective mechanism of ANP against pathologic hyperpermeability and suggests a novel pharmacological intervention for the prevention of increased vascular leak via PAK1-dependent modulation of GEF-H1 activity.
authors.affiliation: From the Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Tian
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Gawlak
authors.forename: Nicolene
authors.initials: N
authors.lastname: Sarich
authors.forename: Tinghuai
authors.initials: T
authors.lastname: Wu
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
mesh_terms: D000199:Actins / Q000378:metabolism; D055371:Acute Lung Injury / Q000201:enzymology / Q000473:pathology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism* / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011014:Pneumonia / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C577356:ARHGEF2 protein, human; D000199:Actins; D018994:Myosin Light Chains; D064067:Rho Guanine Nucleotide Exchange Factors; D009320:Atrial Natriuretic Factor; D054462:p21-Activated Kinases; D013917:Thrombin; D020830:rac1 GTP-Binding Protein
keywords: Endothelial Dysfunction; Lung Injury; Microtubules; Permeability; Rho GTPases; Signal Transduction; Vascular Biology