RESUMO
AIMS: Animal models showed that angiogenesis is related to abnormal heart development. Our objectives were to ascertain whether a relationship exists between congenital heart defects (CHDs) and angiogenic/anti-angiogenic imbalance in maternal and foetal blood and study the expression of angiogenic factors in the foetal heart. METHODS AND RESULTS: Maternal and cord blood placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were compared in 65 cases of CHD and 204 normal controls. Angiogenic factor expression and markers of hypoxia were measured in heart tissue from 23 CHD foetuses and 8 controls. In the CHD group, compared with controls, plasma PlGF levels were significantly lower (367 ± 33 vs. 566 ± 26 pg/mL; P < 0.0001) and sFlt-1 significantly higher (2726 ± 450 vs. 1971 ± 130 pg/mL, P = 0.0438). Foetuses with CHD had higher cord plasma sFlt-1 (442 ± 76 vs. 274 ± 26 pg/mL; P = 0.0285) and sEng (6.76 ± 0.42 vs. 4.99 ± 0.49 ng/mL, P = 0.0041) levels. Expression of vascular endothelial growth factor (VEGF), sFlt-1, markers of chronic hypoxia, and antioxidant activity were significantly higher in heart tissue from CHD foetuses compared with normal hearts (VEGF, 1.59-fold; sFlt-1, 1.92-fold; hypoxia inducible factor (HIF)-2α, 1.45-fold; HO-1, 1.62-fold; SOD1, 1.31-fold). CONCLUSION: An intrinsically angiogenic impairment exists in CHD that appears to be present in both the maternal and foetal circulation and foetal heart. Our data suggest that an imbalance of angiogenic-antiangiogenic factors is associated with developmental defects of the human heart.
Assuntos
Antígenos CD/metabolismo , Cardiopatias Congênitas/embriologia , Proteínas da Gravidez/metabolismo , Receptores de Superfície Celular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto , Estudos de Casos e Controles , Endoglina , Feminino , Sangue Fetal/química , Feto/metabolismo , Humanos , Neovascularização Fisiológica/fisiologia , Fator de Crescimento Placentário , Gravidez , Complicações Cardiovasculares na Gravidez/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVES: To ascertain whether angiogenic factors are altered in smokers at increased risk of preeclampsia (PE) according to uterine artery Doppler (UAD) assessment. METHODS: Uterine artery mean pulsatility index (PI), maternal placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) serum levels were measured in 125 healthy pregnant women at 24 weeks of gestation. Smoking status was determined based on cotinine levels in maternal blood. RESULTS: Smokers had significantly higher PlGF concentration compared with nonsmokers [median PlGF levels: 575 (511) vs. 277 (259) pg/mL, respectively, p = 0.001]. The differences in PlGF levels were also observed between smokers and nonsmokers within the group of women with abnormal UAD and therefore at high risk of developing PE [median PlGF levels: 472 (434) vs. 235 (169) pg/mL, respectively, p = 0.0005]. In our patient cohort, 16 women developed PE (12.8%), of whom only 3 were smokers [odds ratios (ORs): 0.49; 95% confidence interval (CI) (0.13-1.84)]. In patients who finally developed intrauterine growth restriction, the PlGF/sFlt-1 ratio was significantly higher in the group of smokers compared with that of nonsmokers [0.39 (0.28) vs. 0.13 (0.21), respectively, p = 0.0311]. CONCLUSION: The effect of smoking in reducing the risk of PE may be due to the increase of PlGF and PlGF/sFlt-1 ratio in maternal blood, even among women with abnormal UAD.