Abstract 091: Chronic Vasopressin Infusion: A Novel, Clinically Significant, and Pregnancy-Specific Mouse Model of Preeclampsia
Recently we demonstrated that the late-pregnancy cardiovascular disorder, preeclampsia, is characterized by robust, early and sustained vasopressin (AVP) hypersecretion in all three trimesters of pregnancy in humans. We hypothesize a causative role for elevated AVP in the pathogenesis of preeclampsia. This concept was tested by chronically infusing AVP (0.24 - 240 ng/hr, s.c., or saline vehicle) in wildtype C57BL/6J female mice throughout pregnancy. In pregnant mice, AVP infusion caused pregnancy-specific increases in systolic blood pressure by tail-cuff plethysmography with significant increases in the pregnant cohort (saline n=16: 110±3, vs 24 ng/hr AVP n=11: 120±3 mmHg on GD15/16, P<0.05), but no significant difference in the nonpregnant cohort (saline n=14: 108±3, vs 24 ng/hr AVP n=5: 108±5 mmHg, P>0.05). In addition, the AVP infused mice exhibited increased proteinuria (0.24 ng/hr n=2: 66±73, 2.4 ng/hr n=5: 348±56, 24 ng/hr n=2: 799±297 mg/d, P<0.05), intrauterine growth restriction (saline n=25: 0.78±0.06, vs 24 ng/hr n=65: 0.55±0.03 g/fetus, P<0.05), spontaneous feto-placental unit resorption (saline: 0/65=0%, 0.24 ng/hr: 0/16=0%, 2.4 ng/hr: 2/45=4%, 24 ng/hr 8/73=11%, P<0.05), and maternal renal glomerular endotheliosis by electron microscopy. High doses of AVP reduced rates of successful pregnancy with single-night breeding (saline 8/18=44% vs 240 ng/hr 1/20=5%, P<0.05). These data demonstrate that AVP infusion - which simulates the large sustained increases in AVP secretion during human preeclampsia - is sufficient to induce all the cardinal phenotypes of preeclampsia in pregnant C57BL/6J mice. This identifies AVP infusion as a novel, clinically significant, and pregnancy-specific physiological model of preeclampsia in mice. These data support our hypothesis that AVP hypersecretion during pregnancy may be causative for the development of preeclampsia. Ongoing experiments are aimed at identifying the causes of AVP hypersecretion in human preeclampsia, the target tissues and receptors involved, and the utility of targeting AVP signaling as a novel therapeutic for preeclampsia.
Author Disclosures: M. Santillan: H. Other; Modest; Authors MKS and JLG currently hold a provisional patent addressing the use of copeptin and AVP measurements for the early pregnancy prediction of preeclampsia., Authors MKS and JLG currently hold a second provisional patent addressing the inhibition of the AVP system for the treatment of preeclampsia. No direct financial or other conflicts of interest exist.. D.A. Santillan: None. S.M. Scroggins: None. J.Y. Min: None. J.A. Sangren: None. N.A. Pearson: None. K. Gibson-Corley: None. J.L. Grobe: None.
This research has received full or partial funding support from the American Heart Association, National Center.
- © 2014 by American Heart Association, Inc.