Vasopressin Induces Discrete Symptoms of Preeclampsia through Receptor‐ and Gestational Age‐Specific Mechanisms
Authors: Sandgren Jeremy A , Linggonegoro Danny W , Pearson Nicole A , Perschbacher Katherine J , Santillan Donna A , Scroggins Sabrina M , Gibson‐Corley Katherine N , Pierce Gary L , Santillan Mark K , Grobe Justin L 
Published: November 2023

Preeclampsia (PE) is a common gestational disorder characterized by new onset hypertension, proteinuria, intrauterine growth restriction (IUGR), and renal glomerular endotheliosis (RGE) that presents in the 2nd or 3rd trimester. We have demonstrated that arginine vasopressin (AVP) secretion is elevated as early as the 6th week of gestation in women who later develop PE and also that chronic low‐dose AVP infusion during pregnancy causes elevated systolic blood pressure (SBP), proteinuria, IUGR, and RGE in C57BL/6J mice. Here we further characterize the AVP mouse model of PE and use the model to address the hypothesis that AVP induces individual PE phenotypes through distinct receptor types during distinct phases of gestation. By telemetry, AVP infusion resulted in isolated systolic hypertension, consistent with large elastic artery stiffness. AVP infusion also resulted in significantly increased hypoxia‐inducible factor 1 (HIF1)‐alpha binding to chromatin (saline n=5, 0.31±0.01; AVP n=5, 0.34±0.01 AU, p<0.05) within the placenta, consistent with placental hypoxia. To examine receptor involvement, we infused combinations of saline or AVP (24 ng/hr), with conivaptan (non‐selective V1A/V2 antagonist, 22 ng/hr) or relcovaptan (V1A antagonist, 22 ng/hr) throughout gestation. As previously reported, AVP infusion increased SBP (GD18: saline n=35, 111±1.7; AVP n=23, 119±1.9 mmHg, p<0.01) and proteinuria (saline n=27, 48±4.5; AVP n=28, 67±5.6 mg/mL, p<0.01), caused IUGR (saline n=20, 0.80±0.03; AVP n=20, 0.72±0.03 g/fetus, p=0.055), and RGE. Conivaptan prevented elevations in SBP (n=11, 110±3.5 mmHg, p<0.05 vs AVP), but provided no protection from IUGR (n=3, 0.76±0.05 g/fetus), proteinuria (n=11, 73±12.3 mg/mL) or RGE. Relcovaptan prevented proteinuria (n=15, 45±3.9 mg/mL, p<0.05 vs AVP) and RGE, but had no effect on SBP (n=9, 118±3.2 mmHg) or IUGR (n=16, 0.77±0.05 g/fetus). Preliminary studies with tolvaptan (V2 antagonist, 22 ng/hr) support an attenuation of SBP (GD18: n=4, 114±3.8). To examine timing of AVP action, we infused AVP only up to GD3 or GD10. AVP infusion through GD3 had no significant effect on any measured endpoint, but AVP infusion through GD10 elevated SBP through GD10 (which returned to control levels by GD18) and caused significant proteinuria at GD18 (n=19, 88±9.2 mg/mL, p<0.05 vs saline), in the absence of evidence of RGE by electron microscopy. Overall, these data support the concepts that during pregnancy, elevated AVP causes (i) isolated systolic hypertension, (ii) placental hypoxia, (iii) proteinuria and RGE, and (iv) IUGR. Whereas increased SBP appears to require V2 receptor activation throughout gestation, renal damage involves mid‐gestational V1A receptor activation. These data establish selective timeframes and receptors which mediate the generation of PE phenotypes by AVP. Given that PE phenotypes can be mechanistically dissociated in humans (eg – a diagnosis of PE does not necessitate IUGR or proteinuria and modulating blood pressure does not modify other phenotypes), the current study may explain this mechanistic divergence and identify selective receptor targets to treat individual symptoms.