Hypoxia-inducible factor-1α (HIF-1α) overexpression induces preeclampsia-like manifestations in pregnant mice

Abstract

OBJECTIVE: Preeclampsia affects 5-8% of pregnancies, causing substantial fetal and maternal morbidity and mortality. HIF-1α is a transcription factor upregulated in preeclamptic placentas. However, its role in preeclampsia is unknown. Our objective was to test the hypothesis that HIF-1α overexpression would induce preeclamptic manifestations in pregnant mice.DESIGN: Ten weeks old C57BL/6J pregnant mice were injected via tail-vein on gestational day 8 with either adenovirus expressing HIF-1α (CMV-HIF) (n=12), luciferase (CMV-Luc) (n=8) or saline (n=8).MATERIALS AND METHODS: Blood pressure and urinary protein were measured at regular intervals. Fetal and placental weights were recorded following mice sacrifice on day 18. In addition, blood was collected for complete blood count and chemistry analysis and various organs were extracted for histological analysis.RESULTS: CMV-HIF mice had significantly elevated blood pressure compared to CMV-Luc or saline controls (104.5 ± 6.6 vs. 87.1 ± 3.0 vs. 85.7 ± 4.15 mmHg, p<0.05). In addition, marked proteinuria (2-fold) was measured in CMV-HIF mice compared to controls. Placental and fetal weights of CMV-HIF mice were significantly decreased compared to controls, and their placental histology revealed calcifications and vascular abnormalities. Consistent with preeclampsia, electron microscopy analysis demonstrated glomerular endotheliosis in CMV-HIF mice vs. normal histology in controls. Moreover, liver enzymes were significantly elevated while complete blood count and smear revealed microangiopathic hemolytic anemia and thrombocytopenia in CMV-HIF mice vs. controls, consistent with HELLP-like (hemolysis, elevated liver enzymes, low platelets) syndrome. Serum levels of soluble vascular endothelial growth factor receptor-1 and soluble endoglin were elevated in CMV-HIF mice vs. controls, providing a mechanistic explanation for the observations.CONCLUSION: Our results indicate a potential role for HIF-1α in preeclampsia pathogenesis, suggesting new therapeutic targets for this disease. OBJECTIVE: Preeclampsia affects 5-8% of pregnancies, causing substantial fetal and maternal morbidity and mortality. HIF-1α is a transcription factor upregulated in preeclamptic placentas. However, its role in preeclampsia is unknown. Our objective was to test the hypothesis that HIF-1α overexpression would induce preeclamptic manifestations in pregnant mice. DESIGN: Ten weeks old C57BL/6J pregnant mice were injected via tail-vein on gestational day 8 with either adenovirus expressing HIF-1α (CMV-HIF) (n=12), luciferase (CMV-Luc) (n=8) or saline (n=8). MATERIALS AND METHODS: Blood pressure and urinary protein were measured at regular intervals. Fetal and placental weights were recorded following mice sacrifice on day 18. In addition, blood was collected for complete blood count and chemistry analysis and various organs were extracted for histological analysis. RESULTS: CMV-HIF mice had significantly elevated blood pressure compared to CMV-Luc or saline controls (104.5 ± 6.6 vs. 87.1 ± 3.0 vs. 85.7 ± 4.15 mmHg, p<0.05). In addition, marked proteinuria (2-fold) was measured in CMV-HIF mice compared to controls. Placental and fetal weights of CMV-HIF mice were significantly decreased compared to controls, and their placental histology revealed calcifications and vascular abnormalities. Consistent with preeclampsia, electron microscopy analysis demonstrated glomerular endotheliosis in CMV-HIF mice vs. normal histology in controls. Moreover, liver enzymes were significantly elevated while complete blood count and smear revealed microangiopathic hemolytic anemia and thrombocytopenia in CMV-HIF mice vs. controls, consistent with HELLP-like (hemolysis, elevated liver enzymes, low platelets) syndrome. Serum levels of soluble vascular endothelial growth factor receptor-1 and soluble endoglin were elevated in CMV-HIF mice vs. controls, providing a mechanistic explanation for the observations. CONCLUSION: Our results indicate a potential role for HIF-1α in preeclampsia pathogenesis, suggesting new therapeutic targets for this disease.