**5. The Influence of Fluid Shear Stress on Trophoblast Endocrine Activity**

Soon after implantation, the developing placenta starts producing hormones to adapt the maternal physiology to the progressing pregnancy. The highly differentiated syncytiotrophoblast is the predominant cell type involved in placental hormone synthesis, and thus it is obvious that maternal blood flow may not only affect trophoblast differentiation and metabolism, but also its endocrine activity. Recent studies indicate that fluidic flow induces both, syncytialization and production of the classical pregnancy hormone human chorionic gonadotropin (hCG) in BeWo cells [17]. Moreover, laminar and continuous fluid shear stress of 1 dyn/cm<sup>2</sup> promotes placental growth factor (PGF) upregulation in primary human term trophoblasts, which underwent spontaneous differentiation and fusion during a 48 h pre-culture under static conditions (Table 2, [21]). At the same time, secretion of soluble fms-like tyrosine kinase-1 (sFlt-1)—suggested as a biomarker to predict the risk of developing preeclampsia [37]—was only slightly, but not significantly increased by fluid shear stress [21].

Moreover, fluid shear stress is suggested to affect the intracellular availability of cortisol, a glucocorticoid that is regulated by 11β-hydroxysteroid dehydrogenase enzymes (11β-HSDs). In human trophoblast cells, this has been shown for 11β-HSD2 (encoded by *HSD11B2*), an NAD+-dependent enzyme that oxidizes cortisol to the inactive metabolite cortisone. In JEG-3 cells, a unidirectional flow environment with varying fluid shear stress equal to a maximum of 5 dyn/cm<sup>2</sup> reduced 11β-HSD2 mRNA expression and activity, which was reversed to basal levels by discontinuation of the shear stress [15]. Conversion of cortisol to cortisone by 11β-HSD2 is suggested to protect cells from the growth-inhibiting and/or pro-apoptotic effects of cortisol, particularly during embryonic development. Thus, fluid shear stress could be one of the underlying causes of enhanced cortisol levels and reduced 11β-HSD2 activity in fetal growth retardation [38].
