The role of angiotensin II on placental fractalkine

A well-balanced cross-talk between the growing fetus and the mother is a mandatory prerequisite for successful pregnancy. This cross-talk is regulated by the placenta, which functions as interface between the mother and the fetus by fulfilling a wide spread panel of pregnancy maintaining functions. The placenta itself is regulated by hormones, cytokines, growth factors and components of the maternal renin-angiotensin system that controls blood pressure and fluid balance. The main effector molecule of the renin-angiotensin system is angiotensin II, which acts on angiotensin receptors located on many organs including human placenta. Notably, angiotensin II has been suggested to function as an inflammatory mediator by inducing synthesis of proinflammatory molecules. Amongst these, the chemokine fractalkine has recently attracted increasing attention due to its dual nature, existing both as cell-bound and soluble form. While the cell-bound form promotes intercellular adhesion, the soluble form has chemoattractive activity for certain white blood cells. In this proposal the hypothesis will be tested whether or not angiotensin II can stimulate the synthesis and release of fractalkine in human placenta and moreover, whether this stimulatory effect promotes adhesion and activation of a certain subset of maternal white blood cells. In order to address our hypothesis we will perform experiments using isolated cells and tissue specimens from human placenta, as well as rat models showing increased angiotensin II levels. Since this hypothesis has not been addressed before results arising from this innovative, transnational project could open new mechanistic and therapeutic avenues for pregnancy complications related to a deregulated renin-angiotensin system.

Data from this project suggest that both, the chemokine fractalkine and the angiotensin II receptor type 1 are stably expressed in placenta tissue throughout the first trimester of human pregnancy. However, both are neither correlated with each other nor with maternal age, BMI, and gestational age. Our data show that Angiotensin II transiently deregulates placental fractalkine expression, while the angiotensin II receptor antagonist candesartan partly reverses this effect. Moreover, overexpression of recombinant human fractalkine in trophoblasts increases adhesion of monocytes, which consequently is followed by an increased cytokine release. Hence our obtained data suggest that maternal angiotensin II levels influence placental fractalkine expression, which, in turn, can trigger adhesion of maternal circulating monocyte to the placental surface. Furthermore, the release of soluble fractalkine from human placenta into the maternal circulation can promote the pro-inflammatory status of the maternal non-classical monocyte subpopulation. Our data from mass spectrometry analysis of maternal serum samples suggest that maternal angiotensin is converted to angiotensin IV, possibly acting on placental leucine aminopeptidase, considered as angiotensin-IV-receptor. In contrast, fetal angiotensin acts on the placental angiotensin II receptor type 1. Functional experiments with human trophoblasts suggest that maternal angiotensin IV decreases trophoblastic mitochondrial respiration and increases placental leptin levels. The observation that the placental angiotensin-IV-receptor expression is decreased in the pregnancy pathology preeclampsia suggests a new alternative route in maternal angiotensin signaling, which may contribute to hypertensive disorders in pregnancy. In a small side study within this bilateral joint project, analysis of a transgenic preeclampsia rat model suggests that renal glomerular and tubular functions are affected in the transgenic preeclamptic rat during gestation, but almost all functions recover post-delivery.