Showing papers by "Isabella Caniggia published in 2007"

Human Placental Hypoxia-Inducible Factor-1α Expression Correlates with Clinical Outcomes in Chronic Hypoxia in Vivo

Abstract: Placental hypoxia is causally implicated in fetal growth restriction and preeclampsia, with both occurring more frequently at high altitude (>2700 m; HA). The nuclear transcription factor hypoxia-inducible factor (HIF) may facilitate placental oxygen transport at HA by increasing erythropoiesis and placental angiogenesis. We therefore investigated HIF expression and its regulatory mechanisms in placentas from normal pregnancies at high (3100 m), moderate (1600 m), and sea level (75 m) altitudes. Moderate-altitude and sea level placentas did not differ, but HIF-1α and the von Hippel-Lindau tumor suppressor protein were overexpressed in HA placentas. The ability of von Hippel-Lindau tumor suppressor protein to form the E3 ubiquitin protein ligase complex, required for HIF-1α degradation, was unaltered in HA placentas. mRNA for factor-inhibiting HIF, a negative modulator of HIF-1α transactivation, was increased, but protein levels were diminished. Elevated HIF-1α likely contributed to the significant increase we report in HIF-1α downstream target proteins, transforming growth factor β3 in the placenta, and vascular endothelial growth factor and erythropoietin in the maternal circulation. These circulating markers and lowered birth to placental weight ratios correlated with increased HIF-1α, thereby linking molecular and systemic physiological data. The HA response to chronic hypoxia resembles preeclampsia in several aspects, illustrating the utility of the HA model in understanding placental pathologies.

Hypoxia-inducible factors in the first trimester human lung.

Abstract: Lung development takes place in a relatively low-oxygen environment, which is beneficial for lung organogenesis, including vascular development. Hypoxia-inducible factor (HIF)-1 plays an important role in mediating oxygen-regulated events. HIF-1 is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau (VHL) tumor suppressor protein leads to rapid degradation of the HIF-1alpha subunit. Interaction with VHL requires hydroxylation of HIF-1alpha proline residues by prolyl hydroxylases (PHDs). We investigated the expression of the various components regulating HIF-1alpha stability in first trimester (8-14 weeks) human lungs. Spatial expression was assessed by immunohistochemistry and temporal expression by quantitative PCR. Immunoreactivity for PHD1, PHD3, and seven in absentia homolog (SIAH)1 was noted in the pulmonary epithelium. PHD2 was not expressed in the airway epithelium, but in the lung parenchyma. HIF-1alpha and vascular endothelial growth factor (VEGF) immunoreactivity were primarily detected in the branching epithelium. HIF-2alpha and ARNT proteins localized to the developing epithelium as well as mesenchymal, most likely vascular, structures in the parenchyma. VEGF receptor 2 (VEGFR2) was found in the subepithelium as well as in vascular structures of the mesenchyme. All components of the VEC complex (VHL, NEDD8, and Cullin2) were found in the epithelium. Quantitative PCR analysis demonstrated that VEGF, VEGFR1, HIF-1alpha, HIF-2alpha, ARNT, PHD1, PHD2, PHD3, and SIAH1 gene expression was constant during early pulmonary organogenesis. Cumulatively, the data suggest that the lung develops in a low-oxygen environment that allows for proper vascular development through HIF-regulated pathways.

Effect of chemical stabilizers of hypoxia-inducible factors on early lung development

Abstract: Low oxygen stimulates pulmonary vascular development and airway branching and involves hypoxia-inducible factor (HIF). HIF is stable and initiates expression of angiogenic factors under hypoxia, wh...

Hypoxic switch in mitochondrial myeloid cell leukemia factor-1/Mtd apoptotic rheostat contributes to human trophoblast cell death in preeclampsia.

Abstract: Preeclampsia, a disorder of pregnancy, is characterized by increased trophoblast cell death and altered trophoblast-mediated remodeling of myometrial spiral arteries resulting in reduced uteroplacental perfusion. Mitochondria-associated Bcl-2 family members are important regulators of programed cell death. The mechanism whereby hypoxia alters the mitochondrial apoptotic rheostat is essential to our understanding of placental disease. Herein, myeloid cell leukemia factor-1 (Mcl-1) isoform expression was examined in physiological/pathological models of placental hypoxia. Preeclamptic placentae were characterized by caspase-dependent cleavage of death-suppressing Mcl-1L and switch toward cell death-inducing Mcl-1S. In vitro, Mcl-1L cleavage was induced by hypoxia-reoxygenation in villous explants, whereas Mcl-1L overexpression under hypoxia-reoxygenation rescued trophoblast cells from undergoing apoptosis. Cleavage was mediated by caspase-3/-7 because pharmacological caspase inhibition prevented this process. Altitude-induced chronic hypoxia was characterized by expression of Mcl-1L; resulting in a reduction of apoptotic markers (cleaved caspase-3/-8 and p85 poly-ADP-ribose polymerase). Moreover, in both physiological (explants and high altitude) and pathological (preeclampsia) placental hypoxia, decreased trophoblast syncytin expression was observed. Hence, although both pathological and physiological placental hypoxia are associated with slowed trophoblast differentiation, trophoblast apoptosis is only up-regulated in preeclampsia, because of a hypoxia-reoxygenation-induced switch in generation of proapoptotic Mcl-1 isoforms.

Oxygen regulation of macrophage migration inhibitory factor in human placenta

Abstract: Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine involved in regulation of macrophage function. In addition, MIF may also play a role in murine and human reprod...

Diagnostic compositions and treatment methods for conditions involving tro-phoblast cell death, differentiation, invasion and/or cell fusion and turnover

Abstract: The invention provides a method for diagnosing in a subject a condition requiring modulation of or involving trophoblast cell death, differentiation, invasion, and/or cell fusion and turnover, comprising detecting HIF Iα and the factors which modulate or are modulated by this protein, specifically TGFβ3, sFLT, VEGF, SMAD2, 3 and 7, MtdP, MtdL, MclI 1, MclIc, VHL, SiahI, Siah2, ENG, and PHD. The invention also provides a method for diagnosing or distinguishing in a subject a specific condition requiring modulation of or involving trophoblast cell death, differentiation, invasion, and/or cell fusion and turnover, in particular early onset severe preeclampsia (EPE), late onset preeclampsia (LPE) and mtre-uterme growth restriction (IUGR) comprising detecting HLF Iα and the factors which modulate or are modulated by this protein as defined above.