Protein kinase N3 regulates trophoblast mediated stanniocalcin-1 secretion by SGHEC-7 cells a HUVEC-derived endothelial cell line.

Background and Purpose: The maternal uterine spiral arteries (SpA) undergo significant remodelling in the first weeks of a human pregnancy resulting in loss of both Endothelial cells (EC) and vascular smooth muscle cells and increased blood flow to the developing fetus. Failed or inadequate SpA remodelling is associated with common pregnancy complications such as fetal growth restriction and pre-eclampsia. Although the cellular and molecular basis for this remodelling has not been fully described evidence suggests the pluripotent glycoprotein stanniocalcin-1 (STC-1) may play a role. Experimental approach: In the absence of appropriate animal models, we have used ex vivo immunohistochemistry and in vitro cell culture methods using human derived endothelial and trophoblasts cell lines to investigate the expression and secretion of STC-1 by endothelial cells. Key results : Both TCM and phorbol ester (PMA) stimulated STC-1 secretion by endothelial cells, however although Gö6983, a broad-spectrum inhibitor of PKC only inhibited PMA stimulated STC-1 secretion. Further investigation established the involvement of protein kinase-C related molecule protein kinase N3 (PKN3), and the activation Rac-1 in the mediation of the TCM response. Inhibition of c-Jun NH2-terminal kinase (JNK) significantly reduced the secretion of STC-1 in response to both TCM and PMA induced STC-1, indicating an important point of convergence of these two pathways. Contrary to previous findings in other systems the secretion of STC-1 by EC was negatively regulated by activation of PI 3 -kinase. Conclusion and Implications: This study demonstrates for the first time the involvement two parallel pathways in the regulation of STC-1 expression and secretion by endothelial. Further we present evidence that the regulation of STC-1 in endothelial cells is negatively regulated by PI3 kinase. As evidence is growing implicating STC-1 in a number of physiological and pathophysiological processes, these findings may provide evidence for the future therapeutic targeting of STC-1.