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This Article Full Text Full Text (PDF) All Versions of this Article: 287/4/L649    most recent 00219.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Boer, C. Articles by Sipkema, P. Search for Related Content PubMed PubMed Citation Articles by Boer, C. Articles by Sipkema, P.

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Rho GTPases in Lung Physiology and Disease

Smooth muscle F-actin disassembly and RhoA/Rho-kinase signaling during endotoxin-induced alterations in pulmonary arterial compliance

¹Laboratory for Physiology, Departments of ²Anesthesiology and ³Intensive Care, VU University Medical Center, Institute for Cardiovascular Research Vrije Universiteit, 1081 BT Amsterdam; ⁴Department of Anesthesiology, University Medical Center St. Radboud, 6500 HB Nijmegen; and ⁵Gaubius Laboratory, Netherlands Organization for Applied Scientific Research-Prevention and Health, 2301 CE Leiden, the Netherlands

Submitted 7 July 2003 ; accepted in final form 23 September 2003

Endotoxemia is associated with changed pulmonary vascular function with respect to vasoreactivity, endothelial permeability, and activation of inducible nitric oxide synthase II (NOSII). However, whether altered passive arterial wall mechanics contribute to this endotoxin-induced pulmonary vascular dysfunction is still unknown. Therefore, we investigated whether endotoxin affects the passive arterial mechanics and compliance of isolated rat pulmonary arteries. Pulmonary arteries of pentobarbital-anesthetized Wistar rats (n = 55) were isolated and exposed to Escherichia coli endotoxin (50 µg/ml) for 20 h. Endotoxin increased pulmonary artery diameter and compliance (transmural pressure = 13 mmHg) in an endothelium-, Ca²⁺-, or NOSII-induced NO release-independent manner. Interestingly, the endotoxin-induced alterations in the passive arterial mechanics were accompanied by disassembly of the smooth muscle cell (SMC) F-actin cytoskeleton. Disassembly of F-actin by incubation of control arteries with the cytoskeleton-disrupting agent cytochalasin B or the Rho-kinase inhibitor Y-27632 induced a similar increase in passive arterial diameter and compliance. In contrast, RhoA activation by lysophosphatidic acid prevented the endotoxin-induced alterations in the pulmonary SMC F-actin cytoskeleton and passive mechanics. In conclusion, these findings indicate that disassembly of the SMC F-actin cytoskeleton and RhoA/Rho-kinase signaling act as mediators of endotoxin-induced changes in the pulmonary arterial mechanics. They imply the involvement of F-actin rearrangement and RhoA/Rho-kinase signaling in endotoxemia-induced vascular lung injury.

lung injury; passive mechanical arterial properties; cytoskeleton; Y-27632; lysophosphatidic acid

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