(849.7) sFlt1-Induced Preeclampsia Enhances Cardiovascular Response to Post Partum Hypertensive Stimuli via Smooth Muscle Mineralocorticoid Receptor

Poster Board Number: E7

Lauren Biwer (Tufts Medical Center), Qing Lu (Tufts Medical Center), Jaime Ibarrola (Tufts Medical Center), Alec Stepanian (Tufts Medical Center), Joshua Man (Tufts Medical Center), Brigett Carvajal (Tufts Medical Center), Nicholas Camarda (Tufts Medical Center), Zsuzsanna Zsengeller (Beth Israel Deaconess Medical Center), Ellen Seely (Brigham and Womens Hospital), S. Karumanchi (Cedars Sinai Medical Center), Iris Jaffe (Tufts Medical Center)

Background: Preeclampsia (PE), a syndrome of high blood pressure (BP) and renal damage in late pregnancy, is associated with increased soluble VEGF receptor (sFlt1) and survivors have increased risk of future hypertension and cardiovascular disease.

Hypothesis: Since smooth muscle cell mineralocorticoid receptor (SMC-MR) can be activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure during pregnancy may induce a post-partum state of enhanced vascular sensitivity via SMC-MR activation.

Methods/

Results: A PE model was induced by transient viral expression of sFlt1 in pregnant C57Bl6 mice. Elevated serum sFlt1, BP and glomerular endotheliosis was confirmed which all resolve post-partum. In a small cohort of women with prior PE, we confirm salt sensitivity of BP. Thus, postpartum mice were implanted with telemetric BP monitors and exposed to repeated hypertensive stimuli (high salt and subsequent AngII). Mice with prior PE had a significantly increased BP response to hypertensive stimuli.  Microvascular arteries from mice after PE and hypertensive stimuli had enhanced ex vivo myogenic tone and AngII vasoconstriction. To test the direct impact of sFlt1 on SMC-MR function, cultured SMC (Pac1) were transiently exposed to sFlt1 (24 hours on then off) to mimic the post-PE state. SMC-MR transcriptional activity in response to aldosterone and AngII were significantly increased after sFlt1 exposure as measured by luciferase reporter assay. Target gene expression was also enhanced after sFlt1 exposure. Finally, the role of SMC-MR in the post-PE phenotype was tested in vivo by PE induction in SMC-MR-KO vs MR-intact littermates. Post partum, SMC-MR-KO mice were protected from the PE-induced increase in aortic stiffness, microvascular myogenic tone and AngII vasoconstriction.

Conclusion: sFlt1-induced PE produces a state of enhanced sensitivity to stimuli that may be mediated by increased activation of SMC-MR. These data support the use of MR antagonists to mitigate the increased risk of cardiovascular disease in women exposed to PE.

Support or Funding Information

T32 HL007609 (LAB)

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