Reduced AT₂R Signaling Contributes to Endothelial Dysfunction After Preeclampsia

Background: Women who had preeclampsia (a history of preeclampsia) have a >4-fold risk of developing cardiovascular disease compared with women who had an uncomplicated pregnancy (history of healthy pregnancy). Despite the remission of clinical symptoms after pregnancy, vascular endothelial dysfunction persists postpartum, mediated in part by exaggerated Ang II (angiotensin II)-mediated constriction. However, the role of vasodilatory AT₂Rs (Ang II type 2 receptors) in this dysfunction is unknown. We examined the functional role of AT₂R in the microvasculature postpartum and whether acute activation of AT₂R improves microvascular endothelial function after preeclampsia.

Methods: Overall, 24 women (n=12/group) participated. We measured cutaneous vascular conductance responses to (1) graded infusion of compound 21 (AT₂R agonist; 10^-14-10^-8M) alone or with NG-nitro-l-arginine methyl ester (NO synthase inhibitor; 15 mM) and (2) a standardized local heating protocol in control and 10^-11M compound 21-treated sites. Expression of Ang II receptor subtypes I and II in biopsied venous endothelial cells was quantified using immunofluorescence.

Results: AT₂R-mediated dilation (P<0.01) and the NO-dependent contribution (P=0.003) of this response were reduced in women with a history of preeclampsia. Endothelial AT₂R expression was lower in women with a history of preeclampsia (P<0.01), but there were no differences in endothelial AT₁R (Ang II type 1 receptor) expression (P>0.05). Acute activation of AT₂R during local heating improved endothelium (P<0.01) and NO-dependent (P<0.01) dilation in women with a history of preeclampsia but had no effect in women with a history of healthy pregnancy (both P>0.05).

Conclusions: Reductions in AT₂R-mediated dilation contribute to attenuated or impaired endothelial function in women who had a pregnancy complicated by preeclampsia. Furthermore, AT₂R activation may improve endothelial function through NO-dependent mechanisms in otherwise healthy women who had preeclampsia before the onset of cardiovascular disease.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05937841.