Copeptin, a marker of arginine vasopressin (AVP) secretion, is elevated throughout human pregnancies complicated by preeclampsia (PE), and AVP infusion throughout gestation is sufficient to induce the major phenotypes of PE in mice. Thus, we hypothesized a role for AVP in the pathogenesis of PE. AVP infusion into pregnant C57BL/6J mice resulted in hypertension, renal glomerular endotheliosis, intrauterine growth restriction, decreased placental growth factor (PGF), altered placental morphology, placental oxidative stress, and placental gene expression consistent with human PE. Interestingly, these changes occurred despite a lack of placental hypoxia or elevations in placental fms-like tyrosine kinase-1 (FLT1). Coinfusion of AVP receptor antagonists and time-restricted infusion of AVP uncovered a mid-gestational role for the AVPR1A receptor in the observed renal pathologies, versus mid- and late-gestational roles for the AVPR2 receptor in the blood pressure and fetal phenotypes. These findings demonstrate that AVP is sufficient to initiate phenotypes of PE in the absence of placental hypoxia, and indicate that AVP may mechanistically (independently, and possibly synergistically with hypoxia) contribute to the development of clinical signs of PE in specific subtypes of human PE. Additionally, they identify divergent and gestational time-specific signaling mechanisms that mediate the development of PE phenotypes in response to AVP.
Jeremy A. Sandgren, Guorui Deng, Danny W. Linggonegoro, Sabrina M. Scroggins, Katherine J. Perschbacher, Anand R. Nair, Taryn E. Nishimura, Shao Yang Zhang, Larry N. Agbor, Jing Wu, Henry L. Keen, Meghan C. Naber, Nicole A. Pearson, Kathy A. Zimmerman, Robert M. Weiss, Noelle C. Bowdler, Yuriy M. Usachev, Donna A. Santillan, Matthew J. Potthoff, Gary L. Pierce, Katherine N. Gibson-Corley, Curt D. Sigmund, Mark K. Santillan, Justin L. Grobe
Renal and fetal effects of arginine vasopressin (AVP) and AVP-antagonist coinfusion.