Vasopressin Antagonists Regulate Immune Responses in Preeclampsia
Authors: Scroggins Sabrina M , Santillan Donna A , Peterson Jenna M , Huber‐Keener Kathryn J , Sandgren Jeremy A , Perschbacher Katherine J , Pearson Nicole A , Devor Eric J , Gomendoza Daffney T , Pierce Gary L , Grobe Justin L , Santillan Mark K 
Published: November 2023

The early pathogenesis of preeclampsia (PreE) involves altered T helper (TH) cell populations and elevated inflammatory cytokine production. Consistent with current mouse and human literature, we observed an increase in TH1 and TH17 inflammatory cytokine production with a reduction in the TH2‐associated cytokine IL‐4 in our novel, chronic infusion of vasopressin (AVP) mouse model of PreE. The mechanisms of immune modulation by AVP in pregnancy have not been elucidated. As increased CD4+ T cell activity is involved in the development of PreE, the objective of this study was to determine AVP receptor expression in CD4+ T cells and which receptors play a role in the PreE immune phenotype.

Splenic CD4+ T cells were negatively purified on gestational day 18 from wild‐type C57BL/6J female mice infused with AVP (24 ng/hr or saline s.c.) throughout pregnancy. AVP receptor (AVPR) 1a, 1b, and 2 expression was determined via qPCR normalized to 18S rRNA endogenous control. Mouse CD4+ T cells express all AVP receptors. AVPR2 is the highest expressed receptor in CD4+ T cells isolated from saline (N=7, p<0.05 and AVP‐infused (N=10, p<0.05) dams. Maternal mid‐gestation mononuclear cells isolated from healthy human control or PreE‐affected pregnancies were obtained from the University of Iowa Maternal‐Fetal Tissue Bank (IRB #200910784) and similarly analyzed. As in mouse CD4+ T cells, human control (N=27, p<0.05) and PreE‐affected (N=26, p<0.05) CD4+ T cells most highly express AVPR2. AVPR1a is also highly expressed while AVPR1b is the least expressed. CD4+ T cells from human PreE‐affected women express significantly lower AVPR1a (N=0.23, p<0.05) versus controls.

To evaluate the contribution of specific AVPRs to the PreE immune phenotype, AVP and the AVPR antagonists conivaptan (blocks AVPR1a and AVPR2), relcovaptan (blocks AVPR1a), or nelivaptan (blocks AVPR1b) were infused (22 ng/hour) into dams throughout gestation and cytokines were analyzed via ELISA. Conivaptan (N=5, p<0.05) and nelivaptan (N=5, p<0.05) correct the IL‐4 deficiency in the maternal kidney of PreE dams while relcovaptan (N=5, p=NS) does not. The reduction of IL‐4 production in the placenta of AVP‐infused dams is also corrected by conivaptan (N=5, p<0.05) and nelivaptan (N=5, p<0.05), but not relcovaptan (N=5, p=NS). Interestingly, only relcovaptan (N=5, p<0.05) corrects the increased IL‐17 induced by AVP in the placenta while nelivaptan (N=5, p<0.05) further enhances placental IL‐17.

Here, we demonstrate human and mouse CD4+ T cells express AVPRs and inhibition of AVPRs attenuates the TH2 cytokine suppression and elevated TH17 cytokine production observed in PreE. Although the actions of AVP on the vascular and renal systems are well documented, these novel data suggest AVP differentially acts through specific AVP receptors to mediate immune responses in target organs during PreE.

Support or Funding Information

Department of Obstetrics & Gynecology at the University of Iowa Hospitals &Clinics, The Maternal Fetal Tissue Bank, University of Iowa Hospitals & Clinics, Institute for Clinical and Translational Science (NIH KL2 RR024980‐2 to MKS), The Reproductive Scientist Development Program: NIH K12 HD000849 (MKS), NIHK99/R00 HL098276, and PPG HL084207 (JLG), University of Iowa Carver Collaborative Science Grant (MKS & JLG), University of Iowa Immunology Postdoctoral Training Grant (SMS), AHA Innovation Grant (MKS & JLG), AHA Strategically Focused Research Network Grant (MKS & JLG), AHA Predoctoral Research Fellowship (JAS), AHA Postdoctoral Research Fellowship (SMS), John Warner Maternal Health Grant, Shelly Bridgewater Dreams Foundation Grant (SMS)