Maternal glucocorticoid exposure alters tight junction protein expression in the brain of fetal sheep

Abstract

Sadowska GB, Malaeb SN, Stonestreet BS. Maternal glucocorticoid exposure alters tight junction protein expression in the brain of fetal sheep. Am J Physiol Heart Circ Physiol 298: H179 -H188, 2010. First published October 23, 2009 doi:10.1152/ajpheart.00828.2009.-We examined the expression of tight junction (TJ) proteins in the cerebral cortex, cerebellum, and spinal cord of fetuses after maternal treatment with single and multiple courses of dexamethasone. Ewes received either single courses of four 6-mg dexamethasone or placebo injections every 12 h for 48 h between 104 and 107 days or the same treatment once a week between 76 -78 and 104 -107 days of gestation. TJ protein expression was determined by Western immunoblot analysis on tissue harvested at 105-108 days of gestation. Blood-brain barrier permeability has been previously quantified with the blood-tobrain transfer constant (K i) with ␣-aminoisobutyric acid (39). After a single course of dexamethasone, claudin-5 increased (P Ͻ 0.05) in the cerebral cortex, occludin and claudin-1 increased in the cerebellum, and occludin increased in the spinal cord. After multiple dexamethasone courses, occludin and zonula occludens (ZO)-1 increased in the cerebral cortex, and occludin and claudin-1 increased in the cerebellum. Junctional adhesion molecule-A and ZO-2 expressions did not change. Linear regression comparing K i to TJ proteins showed inverse correlations with claudin-1 and claudin-5 in the cerebral cortex after a single course and ZO-2 in the spinal cord after multiple courses and direct correlations with ZO-1 in the cerebellum and spinal cord after multiple courses. We conclude that maternal glucocorticoid treatment increases the expression of specific TJ proteins in vivo, patterns of TJ protein expression vary after exposure to single and multiple glucocorticoid courses, and decreases in blood-brain barrier permeability are associated with increases in claudin-1, claudin-5, and ZO-2 expression and decreases in ZO-1 expression. In utero glucocorticoid exposure alters the molecular composition of the barrier and affects fetal blood-brain barrier function.blood-brain barrier; dexamethasone; steroids THE BLOOD-BRAIN BARRIER is composed of a continuous layer of cerebrovascular endothelial cells connected by intercellular tight junctions (TJs) (4). TJs are composed of transmembrane and associated cytoplasmic proteins (22). The transmembrane proteins include occludin, claudins, and junctional adhesion molecules (JAMs). The proteins of the claudin family form the primary seal between adjacent endothelial cells, whereas occludin is an important support molecule that increases electrical resistance across the barrier and decreases paracellular permeability (22). JAMs regulate TJ formation and leukocyte and endothelial cell interactions (13). The associated cytoplasmic proteins zonula occuldens (ZO)-1 and ZO-2 stabilize TJs by connecting them to actin (22).Maternally administered glucocorticoids have been widely used to accelerate fetal maturation (9,12,30,34). Th...

Inhibition of prolactin with bromocriptine for 28days increases blood–brain barrier permeability in the rat

“…Its formation and function is regulated by several key factors like VEGF and Wnt (Tam and Watts, 2010;Liebner et al, 2011), and is influenced by hormones as well (Cucullo et al, 2004;Kang et al, 2006;Muresanu et al, 2010;Sadowska et al, 2010;Rosas-Hernandez et al, 2013a;Salvador et al, 2014). Here we show for the first time that inhibition of PRL with Bromo increases the permeability the BBB in vivo through the expression of the TJ proteins claudin-5 and occludin.…”

“…These molecules are key factors in the development and acquisition of the BBB phenotype (Liebner et al, 2008;Tam and Watts, 2010). In addition, it has been reported that glucocorticoids (Sadowska et al, 2010;Salvador et al, 2014) and hormones like estrogens (Kang et al, 2006), growth hormone (GH) (Muresanu et al, 2010) and prolactin (PRL) (Rosas-Hernandez et al, 2013a,b) can modulate different features of the BBB both in vitro (Cucullo et al, 2004;Rosas-Hernandez et al, 2013a,b) and in vivo (Kang et al, 2006;Muresanu et al, 2010). These last two hormones are members of the PRL family.…”

Maternal treatment with glucocorticoids modulates gap junction protein expression in the ovine fetal brain

“…The samples of fetal brain in this study were obtained from animals enrolled in our previous studies (Hai et al, 2002, Kerzner et al, 2002, Stonestreet et al, 2004, Sadowska et al, 2006, Sadowska et al, 2010). The surgical and experimental procedures have been previously reported (Stonestreet et al, 1996, Sadowska et al, 2006).…”

“…In addition, we have shown that this maternal treatment affects several proteins critical to CNS homeostasis in the fetal brain including tight junction proteins and Na + ,K + -ATPase (Malaeb et al, 2009, Mehter et al, 2009, Sadowska et al, 2010). Tight junction proteins are well known to be vital constituents of the endothelial tight junction, which regulate blood-brain barrier function (Abbott et al, 2010).…”

Ischemic-Reperfusion Injury Increases Matrix Metalloproteinases and Tissue Metalloproteinase Inhibitors in Fetal Sheep Brain

“…Experimental densitometry values for gelatinolytic activity in each study group were normalized to the average of 3 adult cerebral cortical samples. The densitometry readings of the protein expression were normalized to the average protein expression of the 3 IC values on each immunoblot, as previously described [4,34,35,40]. The final values represent an average of the IOD values obtained from at least 2 different immunoblots and are shown as a ratio to IC.…”