Local angiotensin-(1–7) administration improves microvascular endothelial function in women who have had preeclampsia

Abstract

Despite remission of clinical symptoms postpartum, women who have had preeclampsia demonstrate microvascular endothelial dysfunction, mediated in part by increased sensitivity to angiotensin II (ANG II). Angiotensin-(1–7) [Ang-(1–7)] is an endogenous inhibitor of the actions of ANG II and plausible druggable target in women who had preeclampsia. We therefore examined the therapeutic potential of Ang-(1–7) in the microvasculature of women with a history of preeclampsia (PrEC; n = 13) and parity-matched healthy control women (HC; n = 13) hypothesizing that administration of Ang-(1–7) would increase endothelium-dependent dilation and nitric oxide (NO)-dependent dilation and decrease ANG II-mediated constriction in PrEC. Using the cutaneous microcirculation, we assessed endothelium-dependent vasodilator function in response to graded infusion of acetylcholine (ACh; 10 7 to 102 mmol/L) in control sites and sites treated with 15 mmol/L NG-nitroL-arginine methyl ester (L-NAME; NO-synthase inhibitor), 100 μmol/L Ang-(1–7), or 15 mmol/L L-NAME + 100 μmol/L Ang-(1–7). Vasoconstrictor function was measured in response to ANG II (10 20-10 4 mol/L) in control sites and sites treated with 100 μmol/L Ang-(1–7). PrEC had reduced endothelium-dependent dilation (P < 0.001) and NO-dependent dilation (P = 0.04 vs. HC). Ang-(1–7) coinfusion augmented endothelium-dependent dilation (P < 0.01) and NO-dependent dilation (P = 0.03) in PrEC but had no effect in HC. PrEC demonstrated augmented vasoconstrictor responses to ANG II (P < 0.01 vs. HC), which was attenuated by coinfusion of Ang-(1–7) (P < 0.001). Ang-(1–7) increased endothelium-dependent vasodilation via NO synthase-mediated pathways and attenuated ANG II-mediated constriction in women who have had preeclampsia, suggesting that Ang-(1–7) may be a viable therapeutic target for improved microvascular function in women who have had a preeclamptic pregnancy.