Biphasic effects of 17‐β‐estradiol on expression of occludin and transendothelial resistance and paracellular permeability in human vascular endothelial cells

Abstract

Tight junctions govern the paracellular permeability of endothelial and epithelial cells. Aberrations of tight junction function are an early and key event during the vascular spread of cancer and inflammation. This study sought to determine the role of estrogen in the regulation of tight junctions and expression of molecules making tight junctions in endothelial cells. Human endothelial cell, HECV, which express ER-beta but not ER-alpha was used. 17-beta-estradiol induced a concentration- and time-dependent biphasic effect on tight junction. At 10(-9) and 10(-6) M, it decreased the level of occludin and increased in paracellular permeability of HECV cells, but at 10(-12) M it decreased in paracellular permeability and increased the level of occludin. The transendothelial electrical resistance (TER), however, was reduced by 17-beta-estradiol at lower concentrations (as low as 10(-12) M). Furthermore, the time-dependent biphasic effect was observed over a period of 4 days, with the first reduction of TER seen within 15 min and the second drop occurring 48 h after 17-beta-estradiol treatment. It was further revealed that protein and mRNA levels of occludin, but not claudin-1 and -5, and ZO-1, were reduced by 17-beta-estradiol, in line with changes of TER. This study shows that 17-beta-estradiol can induce concentration- and time-related biphasic effects on tight junction functions expression of occludin in endothelial cells and that this perturbation of tight junction functions may have implications in the etiology of mastalgia and the vascular spread of breast cancer.

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

“…The Y-box is present in the promoters of genes encoding HER2 and several cell cycle regulators, which operate in a cell density-dependent manner [5,36,37]. Transepithelial resistance and paracellular permeability studies in human vascular endothelial (HUVEC) cell monolayers overexpressing ZO-1 and/or ZONAB demonstrated that the two proteins functionally interact at the HER2 promoter [38], suggesting that they might be part of a signaling system that could regulate epithelial differentiation, proliferation, and paracellular permeability in normal and transformed cells.…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…E 2 , 2-ME, and isoflavones enhance endothelial barrier function and reduce its permeability to pro-atherogenic factors such as native and oxidized LDLs (Carbajal & Schaeffer 1998, Delarue et al 1998, Fujimoto et al 1998, Gardner et al 1999, Chi et al 2004, Liu et al 2005, Sumanasekera et al 2007, Dubey & Jackson 2009). The latter effect depends on the modulation of tight junction proteins such as occludin and/or claudin and is mediated via both ERa and ERb (Ye et al 2003, Burek et al 2010, Sandoval & Witt 2011. Furthermore, estrogens promote endothelial cell proliferation and survival.…”

Ultrastructure and Estrogen Regulation of the Lymphatic Stomata of Ovarian Bursa in Mice

“…Heinrich et al (1999) demonstrated that estrogen promoted a nonadherent phenotype through negative regulation of N-cadherin-mediated cell-cell adhesion by the signaling pathway of estrogen receptor, whereas the treatment of antiestrogen is associated with the presence of adherens junctions. The down-regulation of estrogen receptor induced by estrogen treatment can alter the distribution and constitution of cell junction proteins, such as ZO-1, occludin, claudin-1, E-cadherin, and F-actin, which subsequently disassembles the cell-cell contacts (RothenRutishauser et al, 2002;Ye et al, 2003). Therefore, it is possible that cell junction may be involved in the regulation of the opening area of lymphatic stomata by estrogen.…”