Role of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC₂₀pathway in septic rats

Abstract

of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC20 pathway in septic rats. Am J Physiol Lung Cell Mol Physiol 309: L1323-L1332, 2015. First published September 4, 2015 doi:10.1152/ajplung.00016.201543 has been shown to participate in several cardiovascular diseases. Increased vascular permeability is a common and severe complication in sepsis or septic shock. Whether or not Cx43 takes part in the regulation of vascular permeability in severe sepsis is not known, and the underlying mechanism has not been described. With cecal ligation and puncture-induced sepsis in rats and lipopolysaccharide (LPS)-treated vascular endothelial cells (VECs) from pulmonary veins, the role of Cx43 in increased vascular permeability and its relationship to the RhoA/Rock1 pathway were studied. It was shown that vascular permeability in the lungs, kidneys, and mesentery in sepsis rats and LPS-stimulated monolayer pulmonary vein VECs was significantly increased and positively correlated with the increased expression of Cx43 and Rock1 in these organs and cultured pulmonary vein VECs. The connexin inhibitor carbenoxolone (10 mg/kg iv) and the Rock1 inhibitor Y-27632 (2 mg/kg iv) alleviated the vascular leakage of lung, mesentery, and kidney in sepsis rats. Overexpressed Cx43 increased the phosphorylation of 20-kDa myosin light chain (MLC 20) and the expression of Rock1 and increased the vascular permeability and decreased the transendothelial electrical resistance of pulmonary vein VECs. Cx43 RNA interference decreased the phosphorylation of MLC20 and the expression of Rock1 and decreased LPS-stimulated hyperpermeability of cultured pulmonary vein VECs. The Rock1 inhibitor Y-27632 alleviated LPS-and overexpressed Cx43-induced hyperpermeability of monolayer pulmonary vein VECs. This report shows that Cx43 participates in the regulation of vascular permeability in sepsis and that the mechanism is related to the Rock1-MLC20 phosphorylation pathway. connexin 43; vascular permeability; sepsis; RhoA/Rock1 pathway; MLC 20

Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure

“…We sought to identify proteins that are aberrantly expressed in stage 0 lesions that promote BBB hyperpermeability and enable lesion maturation. Aberrant elevation of Cx43 protein has recently been linked to increased barrier permeability (10, 11). Immunofluorescence staining of Cx43 in ccm3 +/– p53 –/– lesions revealed dramatically increased Cx43 expression in all lesion stages, particularly at stage 0, which correlates with lesion progression (Pearson coefficient r = 0.7074; P < 0.01; Fig.…”

“…Cx family members display tissue‐specific expression, with Cx37, Cx40, and Cx43 expressed in brain endothelia (8, 9). Aberrant elevation of Cx43 protein has recently been shown to be detrimental to barrier integrity, but whether this effect is dependent on Cx43 GJs or other functions of Cx43, including hemichannels (HCs) that do not directly oppose another Cx43 channel, has not been thoroughly described (10, 11).…”

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

“…Barrier dysfunction is associated with increased accumulation of Cx43 at the cell membrane and increased gap junction formation facilitating barrier leakage and activating signaling pathways, which support barrier permeability. 132 Redistribution of junctional proteins can lead to new functions. JAM-A redistribution via macropinocytosis and translocation to the apical (luminal) membrane of brain endothelial cells is associated with the role of JAM-A as a leukocyte adhesion molecule governing leukocyte infiltration in inflammation-and stroke-induced BBB dysfunction.…”

The role of gap junctions in inflammatory and neoplastic disorders (Review)

“…Cx43 expression is upregulated in lung epithelium and vascular endothelium (51), and was found to be positively correlated with increased pulmonary vascular permeability in many disease states (41), such as acute inflammation induced by radiation (52) and bacterial sepsis (53,54). In contrast, decreased Cx43 expression in chronic pulmonary diseases such as cystic fibrosis and idiopathic pulmonary fibrosis, was attributed to aberrant Cx43 transport and reduced Cx43 mRNA levels, respectively (55,56).…”

“…It is also being investigated for its potential protective effects in pulmonary inflammatory diseases (41). Expression of various connexins in pulmonary endothelial and smooth muscle cells can be interfered with by using siRNA (54,59), which can potentially be exploited to treat pulmonary inflammatory diseases (41). …”