Experimental preeclampsia results in post‐partum sensitivity to hypertensive stimuli
Authors: Biwer Lauren , Carvajal Brigett , Man Joshua , Zsengeller Zsuzsanna , Karumanchi S. Ananth , Jaffe Iris 
Published: April 2020

Preeclampsia (PE) is a syndrome of new onset high blood pressure (BP) with renal damage during late pregnancy that is associated with increased circulating anti‐angiogenic proteins, including soluble VEGF receptor (sFlt1). Women exposed to PE have increased risk of future cardiovascular disease, including hypertension, with evidence of a “hyper‐responsive” renin‐angiotensin‐aldosterone system (RAAS) persisting post‐partum. Aldosterone (Aldo) and angiotensin II (AngII) can activate vascular smooth muscle cell mineralocorticoid receptor (SMC‐MR), causing changes in gene transcription that contribute to increased BP. Thus, we hypothesized that exposure to increased sFlt1 during pregnancy may induce a state of persistent sensitivity to hypertensive stress by enhanced SMC‐MR activity post‐partum
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We established a model that reproduces the hallmarks of PE by viral overexpression of sFlt1 compared to control virus in pregnant C57Bl6 mice. Using telemetry to measure blood pressure, we demonstrate that sFlt1 injection results in increased serum sFlt1, elevated BP and glomerular endotheliosis, the hallmark of PE‐induced renal damage, in late pregnancy that all resolve post‐partum. Two months post‐partum, wire myography studies performed on 3rd order mesenteric resistance vessels ex vivo reveal that sFlt1‐injected females (“prior‐PE”) have a vasoconstrictor sensitivity to AngII (1e‐9 dose: 0.16mN vs. 1.42mN, p=0.059) . To test whether prior PE results in increased sensitivity to hypertensive stimuli, post‐partum mice were exposed to various high salt diet conditions or to a moderate pressor dose of AngII (600mg/kg/day infusion) while BP was monitored via telemetry. Mice with prior PE had a trend toward an increased peak BP in response to 2% sodium (11.71mmHg vs. 3.62mmHg, p=0.09) and a significantly increased BP response to 4% sodium (8.88mmHg vs 5.34mmHg, p<0.05). Prior PE mice also had a significantly enhanced BP response to AngII versus those with normotensive pregnancies (22.83 mmHg vs 4.46 mmHg, p=0.0005). Plasma Aldo measured via radioimmunoassay tended to be higher in mice with prior PE (4.65nM vs 2.09nM, P=0.08). Since SMC‐MR can be activated by AngII, we investigated the extent of AngII‐induced SMC‐MR activation after PE using qPCR to measure known SMC‐MR target genes. In microvessels from mice with prior PE, mRNA expression showed increased AT1R (relative expression 3.69 vs 1.30, p<0.05), Cav1.2 (2.29 vs 1.11, p=0.06) and PlGF (1.92 vs 1.20, p=0.11). Studies are underway to determine whether SMC‐specific deletion of MR or post‐partum pharmacologic MR inhibition can protect against enhanced BP sensitivity to AngII and high salt diet after sFlt1‐induced PE.

sFlt1‐induced PE produces a state of enhanced sensitivity to hypertensive stimuli that may be mediated by increased activation of SMC‐MR. If confirmed, these data support the use of spironolactone as a therapy to mitigate the increased risk of cardiovascular disease in women exposed to PE.

Support or Funding Information

NIH T32HL007609 (LAB), NIH R25GM066567 (BVC)