RESUMO
Preeclampsia (PE) is a pregnancy-specific disorder characterized by sudden onset of hypertension and proteinuria in the second half of pregnancy (>20 wk). PE is strongly associated with abnormal placentation and an excessive maternal inflammatory response. Galectin-1 (Gal-1), a member of a family of carbohydrate-binding proteins, has been shown to modulate several processes associated with placentation and to promote maternal tolerance toward fetal antigens. Here, we show that Gal-1 exhibits proangiogenic functions during early stages of pregnancy, promoting decidual vascular expansion through VEGF receptor 2 signaling. Blocking Gal-1-mediated angiogenesis or lectin, galactoside-binding, soluble, 1 deficiency results in a spontaneous PE-like syndrome in mice, mainly by deregulating processes associated with good placentation and maternal spiral artery remodeling. Consistent with these findings, we observed a down-regulation of Gal-1 in patients suffering from early onset PE. Collectively, these results strengthen the notion that Gal-1 is required for healthy gestation and highlight Gal-1 as a valuable biomarker for early PE diagnosis.
Assuntos
Galectina 1/fisiologia , Neovascularização Fisiológica/fisiologia , Pré-Eclâmpsia/etiologia , Animais , Modelos Animais de Doenças , Feminino , Galectina 1/metabolismo , Humanos , Camundongos , Placenta/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Trofoblastos/citologiaRESUMO
INTRODUCTION: Cystathionine-b-synthase (CBS) produces the vasodilatory and anti-inflammatory hydrogen sulfide (H2S) by conversion of homocysteine (Hcy). H2S is involved in placental vascular tone regulation. Previously, we showed that woman with PE have hyperhomocysteinemia and decreased placental CBS gene expression. OBJECTIVES: Aberrant CBS gene expression may play a role in hyperhomocysteinemia and decreased H2S and could be involved in pathogenesis of PE. We studied whether the presence of CBS single nucleotide polymorphisms (SNPs) is associated with the development of PE. METHODS: Six CBS SNPs (rs12329764, rs2851391, rs234713, rs234706, rs1789953, rs11203172) were genotyped in 99 controls, 60 severe, and 39 mild PE cases. Severe and mild PE cases were additionally subdivided into late- (>34 weeks) and early-onset (<34 weeks) PE. The association of the alleles with development PE was tested with logistic regression. RESULTS: Two of the six SNPs are associated with PE. The minor allele for rs11203172 reduces the risk for developing severe PE (OR[95% CI]=0.54[0.21-0.94], p=0.023). The minor allele for rs234706, which is associated with low Hcy, increased the risk to develop mild, late-onset PE (2.10[1.15-3.85], p=0.016). CONCLUSION: SNPs in the CBS gene are associated with risk of developing PE. Within the CBS gene, SNPs associated with both a decreased and an increased risk to develop PE were found. Altered effectiveness of CBS may affect PE through decreased H2S production or Hcy accumulation.