Both of these hormones are thus vulnerable if normal ER function is perturbed, and so feto-maternal signalling and the capacity of the placenta to influence maternal metabolism may be impaired. This may restrict the supply of glucose and free fatty acids to the placenta. The syncytiotrophoblast also expresses a wide array of receptors that are involved in signalling and the transport of nutrients. As these are membrane proteins they will be processed by the ER, and so their conformation Selleckchem Alectinib and activity are potentially compromised during ER stress. The release of apoptotic debris from the surface

of the syncytiotrophoblast is one of the many factors that has been implicated in the second stage of the two-stage model of pre-eclampsia [3]. Onalespib mouse Microvillous particles and placental debris are highly irritant to endothelial cells in vitro, leading to activation and an inflammatory response [48]. Apoptosis is increased in the trophoblast in early-onset pre-eclampsia [49], and ER stress provides at least two potential pathways to mediate this effect, activation of CHOP and of caspase 4. We have observed evidence of both pathways in placentas from early-onset pre-eclampsia, and localised them immunohistochemically to the syncytiotrophoblast and the fetal endothelial

cells ( Fig. 2). The former may be responsible for increased shedding of placental debris from the syncytiotrophoblast layer, whereas the latter may adversely impact on the development and maintenance of the placental capillary network. A major advance in our understanding of the pathophysiology of pre-eclampsia came with the recognition that the syndrome is associated with a heightened maternal inflammatory response [1] and [50]. Maternal circulating levels of TNF-α and interleukin 6 are increased in pre-eclampsia [51], and both these cytokines will cause endothelial cell activation. Evidence of such activation is provided by the finding of Chlormezanone elevated levels of long pentraxin 3, a marker for inflammation involving a vascular bed,

in women with pre-eclampsia [52]. There are close links between ER stress and activation of pro-inflammatory responses that may be mediated by various pathways [53]. Firstly, the kinase domain of Ire1 can activate the p38 MAPK, JNK and NFκB pathways as previously described [54]. Secondly, protein synthesis inhibition independently leads to activation of the NFκB pathway since the half-life of the inhibitory sub-unit, IκB, is much shorter than that of NFκB [55]. Thirdly, the ER produces ROS as a by-product of protein folding, and this may be accentuated during repeated attempts to refold misfolded proteins. ROS can activate the NFκB pathway by stimulating phosphorylation of the IκB sub-unit, targeting it for degradation.