Tyagi Neetu, Roberts Andrew M, Dean William L, Tyagi Suresh C, Lominadze David
Department of Physiology and Biophysics, Health Sciences Center, A-1115, University of Louisville, Louisville, KY 40292, USA.
Mol Cell Biochem. 2008 Jan;307(1-2):13-22. doi: 10.1007/s11010-007-9579-2. Epub 2007 Sep 12.
Many cardiovascular and cerebrovascular disorders are accompanied by an increased blood content of fibrinogen (Fg), a high molecular weight plasma adhesion protein. Fg is a biomarker of inflammation and its degradation products have been associated with microvascular leakage. We tested the hypothesis that at pathologically high levels, Fg increases endothelial cell (EC) permeability through extracellular signal regulated kinase (ERK) signaling and by inducing F-actin formation. In cultured ECs, Fg binding to intercellular adhesion molecule-1 and to alpha(5)beta(1) integrin, caused phosphorylation of ERK. Subsequently, F-actin formation increased and coincided with formation of gaps between ECs, which corresponded with increased permeability of ECs to albumin. Our data suggest that formation of F-actin and gaps may be the mechanism for increased albumin leakage through the EC monolayer. The present study indicates that elevated un-degraded Fg may be a factor causing microvascular permeability that typically accompanies cardiovascular and cerebrovascular disorders.
许多心血管和脑血管疾病都伴随着纤维蛋白原（Fg）血液含量的增加，Fg是一种高分子量血浆粘附蛋白。Fg是炎症的生物标志物，其降解产物与微血管渗漏有关。我们测试了这样一个假设：在病理高水平下，Fg通过细胞外信号调节激酶（ERK）信号传导并诱导F-肌动蛋白形成来增加内皮细胞（EC）的通透性。在培养的内皮细胞中，Fg与细胞间粘附分子-1和α(5)β(1)整合素结合，导致ERK磷酸化。随后，F-肌动蛋白形成增加，并与内皮细胞之间间隙的形成同时出现，这与内皮细胞对白蛋白通透性增加相对应。我们的数据表明，F-肌动蛋白和间隙的形成可能是白蛋白通过内皮细胞单层渗漏增加的机制。本研究表明，未降解的Fg升高可能是导致微血管通透性增加的一个因素，而微血管通透性增加通常伴随心血管和脑血管疾病。
