TY - JOUR
T1 - Effects of hypoxia-inducible factor-1α overexpression in pregnant mice
T2 - Possible implications for preeclampsia and intrauterine growth restriction
AU - Tal, Reshef
AU - Shaish, Aviv
AU - Barshack, Iris
AU - Polak-Charcon, Silvia
AU - Afek, Arnon
AU - Volkov, Alexander
AU - Feldman, Boris
AU - Avivi, Camila
AU - Harats, Dror
PY - 2010/12
Y1 - 2010/12
N2 - Preeclampsia and intrauterine growth restriction (IUGR) are pregnancy-specific disorders that share a common pathophysiology. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays an important role in placental development. HIF-1α 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-1α overexpression on pregnancy in mice. C57BL/6J pregnant mice were systemically administered either adenovirus expressing stabilized HIF-1α (cytomegalovirus [CMV]-HIF), luciferase control (CMV-Luc), or saline on gestational day 8. Pregnant mice overexpressing HIF-1α had significantly elevated blood pressure and proteinuria compared with pregnant controls. HIF-1α mice showed fetal IUGR, decreased 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-1α in the pathogenesis of both preeclampsia and IUGR.
AB - Preeclampsia and intrauterine growth restriction (IUGR) are pregnancy-specific disorders that share a common pathophysiology. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays an important role in placental development. HIF-1α 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-1α overexpression on pregnancy in mice. C57BL/6J pregnant mice were systemically administered either adenovirus expressing stabilized HIF-1α (cytomegalovirus [CMV]-HIF), luciferase control (CMV-Luc), or saline on gestational day 8. Pregnant mice overexpressing HIF-1α had significantly elevated blood pressure and proteinuria compared with pregnant controls. HIF-1α mice showed fetal IUGR, decreased 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-1α in the pathogenesis of both preeclampsia and IUGR.
UR - http://www.scopus.com/inward/record.url?scp=78650222706&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2010.090800
DO - 10.2353/ajpath.2010.090800
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AN - SCOPUS:78650222706
SN - 0002-9440
VL - 177
SP - 2950
EP - 2962
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -