Preeclampsia, the Renin-Angiotensin-Aldosterone System and beyond

Abstract

The renin-angiotensin-aldosterone system (RAAS) plays an essential role in the regulation of blood pressure and body fluid homeostasis, but also contributes importantly to the pathophysiology of hypertension, renal disease and heart failure. Clinically, the RAAS is of great interest as inhibition at different levels has been proven to be an effective therapy for hypertension, cardiovascular and renal disease. Angiotensin II mediates its effects via angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2) receptors. AT1-receptors are widely expressed throughout the body and mediate the well-known effects of angiotensin II, including vasoconstriction, sympathetic nervous system activation and sodium and water retention. While experimental studies show that stimulation of the AT2-receptor counteracts these effects by inducing vasorelaxation and natriuresis in healthy animals, our knowledge about AT2-receptor function in humans is limited to a few studies, showing, at most, modest vasodilatory effects upon AT2-receptor stimulation. In contrast to the beneficial effects, recent studies suggest that the AT2-receptor function might become deleterious (e.g., becoming pro-hypertensive and pro-hypertrophic) in the diseased state.2, 3 In our study in women with preeclampsia we found a greater angiotensin II vasoconstrictor response in isolated small arteries than in the arteries of normal pregnant women, which was due to constrictor AT2-receptors. The mechanism behind this change from dilator to constrictor function is unknown, but may involve a reduced NO availability due to endothelium dysfunction, heterodimerisation with other vasoconstrictor receptors (including the AT1-receptor) and/or a different location of the AT2-receptor (vascular smooth muscle cells versus endothelial cells).

In the past decade C21, a selective AT2-receptor agonist, has been developed that could help to clarify these issues. However, despite overwhelming data supporting AT2-receptor-mediated vasodilation, for instance in the preparations investigated in Chapter 3, we were unable to demonstrate AT2-receptor agonistic vasodilation in response to the C21 in rat, mouse, and human vessels. However, we found support for C21-induced vasorelaxation, but in an AT receptor-independent manner, possibly by preventing calcium influx into the cell. Furthermore, we found that C21 is capable of activating AT1-receptors, resulting in vasoconstriction. This combination of vasorelaxant and vasoconstrictor effects of C21 can provide an explanation for both the hypertensive and hypotensive effects of C21 demonstrated in in vivo models.