Defective angiogenesis in hypoplastic human fetal lungs correlates with nitric oxide synthase deficiency that occurs despite enhanced angiopoietin-2 and VEGF

Author:

Boucherat Olivier123,Franco-Montoya Marie-Laure124,Delacourt Christophe124,Martinovic Jelena56,Masse Virginie57,Elie Caroline57,Thébaud Bernard8,Benachi Alexandra1259,Bourbon Jacques R.124

Affiliation:

1. Institut Mondor de Recherche Biomédicale, Institut National de la Santé et de la Recherche Médicale Unité 955; and

2. Faculté de Médecine, Université Paris 12, Créteil, France;

3. Centre de Recherche en Cancérologie de L'Hôtel-Dieu de Québec, Université Laval, Québec, Canada;

4. PremUP;

5. Université Paris Descartes;

6. Service de Fœtopathologie, Assistance Publique-Hôpitaux de Paris et Hôpital Necker-Enfants Malades; and

7. Service de Biostatistique et Informatique Médicale, Assistance Publique-Hôpitaux de Paris et Hôpital Necker-Enfants Malades, Paris, France;

8. Department of Pediatrics, Division of Neonatology, Vascular Biology Group, University of Alberta, Edmonton, Alberta, Canada; and

9. Maternité, Assistance Publique-Hôpitaux de Paris et Hôpital Necker-Enfants Malades, Paris, France

Abstract

Lung hypoplasia (LH) is a life-threatening congenital abnormality with various causes. It involves vascular bed underdevelopment with abnormal arterial muscularization leading to pulmonary hypertension. Because underlying molecular changes are imperfectly known and sometimes controversial, we determined key factors of angiogenesis along intrauterine development, focusing at the angiopoietin (ANG)/Tie-2 system. Lung specimens from medical terminations of pregnancy (9–37 wk) were used, including LH due to congenital diaphragmatic hernia (CDH) or other causes, and nonpulmonary disease samples were used as controls. ELISA determination indicated little ANG-1 change during pregnancy and no effect of LH, whereas Tie-2 declined similarly between 9 and 37 wk in LH and controls. By contrast, ANG-2 markedly increased in LH from 24 wk, whereas it remained stable in controls. Because VEGF increased also, this was interpreted as an attempt to overcome vascular underdevelopment. Hypothesizing that its inefficiency might be due to impaired downstream mechanism, endothelial nitric oxide synthase (eNOS) was determined by semiquantitative Western blot and found to be reduced by ∼75%, mostly in the instance of CDH. In conclusion, angiogenesis remains defective in hypoplastic lungs despite reactive enhancement of VEGF and ANG-2 production, which could be due, at least in part, to insufficient eNOS expression.

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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