Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia

作者：Lauren A. Biwer, Qing Lu, Jaime Ibarrola, Alec Stepanian, Joshua J. Man, Brigett Carvajal, Nicholas D. Camarda, Zsuzsanna K. Zsengellér, Geraldine Skurnik, Ellen W. Seely, S. Ananth Karumanchi, Iris Z. Jaffe · 发表于：Circulation Research · 年份：2023 · DOI：10.1161/circresaha.122.321228 · 被引用次数：40 · 研究领域：Hormonal Regulation and Hypertension、Sodium Intake and Health、Pregnancy and preeclampsia studies

BACKGROUND: Preeclampsia is a syndrome of high blood pressure (BP) with end organ damage in late pregnancy that is associated with high circulating soluble VEGF receptor (sFlt1 [soluble Fms-like tyrosine kinase 1]). Women exposed to preeclampsia have a substantially increased risk of hypertension after pregnancy, but the mechanism remains unknown, leaving a missed interventional opportunity. After preeclampsia, women have enhanced sensitivity to hypertensive stress. Since smooth muscle cell mineralocorticoid receptors (SMC-MR) are activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure in pregnancy induces a postpartum state of enhanced SMC-MR responsiveness. METHODS: Postpartum BP response to high salt intake was studied in women with prior preeclampsia. MR transcriptional activity was assessed in vitro in sFlt1-treated SMC by reporter assays and PCR. Preeclampsia was modeled by transient sFlt1 expression in pregnant mice. Two months post-partum, mice were exposed to high salt and then to AngII (angiotensin II) and BP and vasoconstriction were measured. RESULTS: Women exposed to preeclampsia had significantly enhanced salt sensitivity of BP verses those with a normotensive pregnancy. sFlt1 overexpression during pregnancy in mice induced elevated BP and glomerular endotheliosis, which resolved post-partum. The sFlt1 exposed post-partum mice had significantly increased BP response to 4% salt diet and to AngII infusion. In vitro, SMC-MR transcriptional activ...