Effects of Hypoxia-Inducible Factor-1α Overexpression in Pregnant Mice Possible Implications for Preeclampsia and Intrauterine Growth Restriction

Preeclampsia and intrauterine growth restriction (IUGR) are pregnancy specific disorders that share a common pathophysiology Hypoxia inducible factor 1 alpha (HIF 1 alpha) is a transcription factor that plays an important role in placental development HIF 1 alpha is elevated in preeclamptic placentas and induces soluble vascular endothelial growth factor receptor 1 (sFLT 1) a central factor in preeclampsia and IUGR pathogenesis Our objective was to investigate the effects of HIF 1 alpha overexpression on pregnancy in mice C57BL/6J pregnant mice were systemically administered either adenovirus expressing stabilized HIF 1 alpha (cytomegalovirus [CMV] HIF) luciferase control (CMV Luc) or saline on gestational day 8 Pregnant mice overexpressing HIF 1 alpha had significantly elevated blood pressure and proteinuria compared with pregnant controls HIF 1 alpha mice showed fetal IUGR de creased placental weights and histopathological placental abnormalities compared with control mice Glomerular endotheliosis the hallmark lesion of preeclampsia was demonstrated in the kidneys of these mice relative to the normal histology in control mice Moreover liver enzyme levels were significantly elevated whereas complete blood counts revealed significant anemia and thrombocytopenia in CMV HIF mice compared with controls Blood smears confirmed microangiopathic hemolytic anemia in CMV HIF mice consistent with HELLP (hemolysis elevated liver enzymes and low platelets) like syndrome CMV HIF mice showed elevation in serum sFLT 1 and soluble endoglin providing a mechanistic explanation for the observations Collectively our results suggest a possible role for HIF 1 alpha in the pathogenesis of both preeclampsia and IUGR. (Am J Pathol 2014 177 2950-2962 DOI 10 2353/ajpath 2010 090800)