Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia

Abstract

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 activity in response to aldosterone or AngII was significantly increased after transient exposure to sFlt1 as was aldosterone-induced expression of AngII type 1 receptor. Post-partum, SMC-MR-KO mice were protected from the enhanced response to hypertensive stimuli after PE. Mechanistically, preeclampsia mice exposed to postpartum hypertensive stimuli develop enhanced aortic stiffness, microvascular myogenic tone, AngII constriction, and AngII type 1 receptor expression, all of which were prevented in SMC-MR-KO littermates. CONCLUSIONS: These data support that sFlt1-induced vascular injury during PE produces a persistent state of enhanced sensitivity of SMC-MR to activation. This contributes to postpartum hypertension in response to common stresses and supports testing of MR antagonism to mitigate the increased cardiovascular risk in women after PE.

Translation of mechanistic advances in preeclampsia to the clinic: Long and winding road

“…231 Furthermore, we have also recently demonstrated that sFlt-1-induced vascular injury in pregnancy produces enhanced sensitivity of smooth muscle cell-mineralocorticoid receptor, contributing to post-partum hypertension in response to common stressors such as salt. 232 Taken together, these data suggest that exposure to high levels of sFlt-1 during pregnancy reprograms the cardiovascular system to "remember" the initial insult and respond accordingly. In this model, it is presumed that this effect is independent of pre-existing cardiovascular risk factors.…”

Role Of The C-C Motif Chemokine Ligand 5 (CCL5) And Its Receptor, C-C Motif Chemokine Receptor 5 (CCR5) In The Genesis Of Aldosterone-induced Hypertension, Vascular Dysfunction, And End-organ Damage

“…The primary function of aldosterone, via mineralocorticoid receptor (MR), is to regulate salt and water homeostasis in the body by acting on the distal tubule and collecting duct of nephrons in the kidney, which in turn leads to sodium and water reabsorption and potassium excretion 1,4,5 . However, MR are expressed in different cell types including vascular smooth muscle cells (VSMC) 6 , endothelial cells 9 , adipocytes that form perivascular adipose tissue 7 , and immune cells 8,9 , where aldosterone can exert its deleterious effects including inflammation, oxidative stress, accelerated fibrosis, and proliferation 4,5,8,[10][11][12][13] . In this context, hyperaldosteronism and hyperactivation of MR signaling are key features in the pathogenesis of diabetes 2,3,10 , obesity 2,3,10 , atherosclerosis 14 , stroke 13 , and hypertension 15 .…”

Prior Exposure to Experimental Preeclampsia Increases Atherosclerotic Plaque Inflammation in Atherogenic Mice—Brief Report

“…21,[26][27][28] Using the sFlt1-induced preeclampsia model in C57Bl/6 mice during pregnancy, we have demonstrated that high circulating sFlt1 results in increased blood pressure and kidney damage in late pregnancy, and the high sFlt1 and resulting syndrome all normalize postpartum, consistent with the human phenotype. 29 Several months postpartum, mice with prior preeclampsia have an increased blood pressure response to high salt intake and enhanced vascular remodeling in response to injury. 29,30 These findings suggest persistent changes, making the vasculature more susceptible to dysfunction even after preeclampsia is resolved.…”

“…29 Several months postpartum, mice with prior preeclampsia have an increased blood pressure response to high salt intake and enhanced vascular remodeling in response to injury. 29,30 These findings suggest persistent changes, making the vasculature more susceptible to dysfunction even after preeclampsia is resolved.…”

“…32 Conversely, the preeclampsia phenotype resolves postpartum in the sFlt1-induced preeclampsia mouse model. 29,30 Combining these models can be leveraged to study whether prior exposure to preeclampsia directly contributes to atherosclerotic responses to hyperlipidemia initiated after pregnancy, without confounding of preexisting risk factors. We hypothesized exposure to the sFlt1-induced preeclampsia model would exacerbate plaque inflammation in response to hyperlipidemia-induced atherosclerosis postpartum.…”