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ENDOCRINE AND DIABETES

High-Glucose-Altered Endothelial Cell Function Involves Both Disruption of Cell-to-Cell Connection and Enhancement of Force Development

Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan

Vascular endothelial cells (ECs), which regulate vascular tonus, serve as a barrier at the interface of vascular tissue. It is generally believed that alteration of this barrier is correlated with diabetic complications; however, a detailed mechanism has not been elucidated. This study examined alteration of bovine arterial EC functions stimulated by a thromboxane A₂ analog (9,11-dideoxy-11,9-epoxymethano prostaglandin F₂; U46619 [GenBank] ) under normal and high-glucose (HG) conditions. U46619 [GenBank] treatment increased EC layer permeability in a time- and dose-dependent fashion. This response initially disrupted calcium-dependent EC-to-EC connections, namely, vascular endothelial cadherin (VE-CaD). Thereafter, EC force development in association with morphological changes was detected employing a reconstituted EC fiber technique, resulting in paracellular hole formation in the EC layer. Thus, we confirmed that U46619 [GenBank] -induced enhancement of EC layer permeability involves these sequential steps. Similar trials were performed using a concentration twice that of normal glucose (22.2 mM glucose for 48 h). This treatment significantly enhanced U46619 [GenBank] -induced EC layer permeability; furthermore, increases in both rate of VE-CaD disruption and EC fiber contraction were evident. Inhibition of calcium-independent protein kinase C and diacylglycerol kinase indicated that the glucose-dependent increase in VE-CaD disruption was mediated by a calcium-independent mechanism. Moreover, EC contraction was regulated by a typical calcium-independent pathway associated with rho kinase and actin stress fiber. Contraction was also enhanced under HG conditions. This investigation revealed that glucose-dependent enhancement of EC layer permeability is related to increases in VE-CaD disruption and EC contraction. Increases in both parameters were mediated by alteration of a calcium-independent pathway.

Address correspondence to: Dr. Koji Nobe, Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-0555, Japan. E-mail: kojinobe{at}pharm.showa-u.ac.jp