Abstract P178: Vasopressin Induces Discrete Symptoms of Preeclampsia Through Receptor- and Gestational Age-specific Mechanisms

Abstract

Preeclampsia (PE) is a common late-gestational disorder characterized by de novo pregnancy specific hypertension, proteinuria, and renal glomerular endotheliosis (RGE). Arginine vasopressin (AVP) secretion (as measured by copeptin) is elevated as early as 6 weeks gestation in pregnancies which later develop PE, and chronic low-dose AVP infusion is sufficient to phenocopy PE in pregnant mice. However, the identity and timeframe of involvement of specific AVP receptors initiating discrete symptoms of PE in this model remain unclear. Wildtype C57BL/6J mice were instrumented with subcutaneous osmotic minipumps to infuse AVP (24 ng/hr) and/or inhibitors during gestation. To clarify the involvement of AVP V 1A and V 2 receptors, one cohort of saline- or AVP-infused pregnant mice was simultaneously infused with the combined V 1A +V 2 antagonist, conivaptan (22 ng/hr). Conivaptan co-treatment ameliorated the hypertension phenotype (SBP on gestational day (GD)15: saline 108.3±2.1, n=24; AVP 120.5±2.1, n=17; conivaptan 112.8±4.1, n=8; AVP+conivaptan 109.8±3.5 mmHg, n=11) but did not prevent proteinuria (on GD17: saline 46.4±6.4, n=15; AVP 79.3±8.5, n=15; conivaptan 64.6±6.7, n=7; AVP+conivaptan 72.9±12.3 mg/mL, n=11) or RGE. To clarify the important timeframes of involvement of AVP for discrete symptoms, subsets of mice were infused with AVP throughout gestation or to only GD10. Continuous infusion of AVP was required to maintain the hypertensive phenotype, as infusion to only GD10 initially elevated blood pressure (SBP at GD10: saline 103.7±1.3, n=26; AVP to GD10 111.5±1.6 mmHg, n=19) but failed to sustain hypertension for the remainder of gestation (SBP at GD15: 112.2±1.3 mmHg, n=19). In contrast, infusion of AVP only to GD10 caused a sustained proteinuria (at GD17: 88.2±9.2 mg/mL, n=19). Infusion of AVP only to GD3 had no effect on any examined endpoint. These data support a specific role for AVP V 1A /V 2 receptors throughout gestation for the hypertension but not proteinuria or RGE phenotypes of PE. Our results therefore indirectly support an early-gestational role for other receptors (perhaps V 1B , cullin-5, or the oxytocin receptor) in the proteinuria and RGE phenotypes of this disorder.