© 2000 American Heart Association, Inc.
Editorials |
Rho, Tyrosine Kinase, Ca2+, and Junctions in Endothelial Hyperpermeability
From the Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, La.
Correspondence to J. Steven Alexander, Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Hwy, PO Box 33932, Shreveport, LA 71130. E-mail jalexa@lsumc.edu
Key Words: thrombin • barrier • permeability • myosin
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Introduction |
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Increased microvascular permeability is a central hallmark of inflammation and the basis of edematous tissue injury in many acute and chronic pathological conditions, including ischemia-reperfusion injury, sepsis, and acute respiratory distress syndrome.1 2 3 4 Increased microvascular leakage may occur in any region of the vasculature, but it is most familiar in the microvasculature, especially the postcapillary venule. Ultrastructurally, anatomists recognize at least 3 types of endothelial cells: continuous, fenestrated, and discontinuous, which can all exhibit altered barrier in response to environmental and chemical factors.
Early studies by Majno and Palade5 and later studies by Simionescu et al6 suggested that inflammatory mediators, such as histamine, thrombin, and serotonin, increase solute permeability in microvessels by enlarging interjunctional spaces and allowing the extravasation of fluid, protein, and leukocytes into the tissues. It is widely held that many inflammatory mediators (eg, thrombin, histamine, and bradykinin) use a common mechanism to control junctional exchange through a Ca2+/calmodulin (CaM) and myosin light chain kinase (MLCK)–regulated actomyosin contraction, which generates cytoskeletal tension. In theory, this tension promotes separation of junctional clefts and allows equilibration of solutes into the interstitium.7 8 9 10 Many recent studies have demonstrated that this contractile response is regulated to a large extent through the activity of several members of the small GTPase family that includes Rho, Rac, and Cdc42.7 8 11 12
The study by van Nieuw Amerongen et al13 in this issue of
Circulation Research is the most recent of several studies
that describe features of Rho-dependent endothelial
permeability produced by mediators, especially thrombin. While Rho is
thought
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