title: [Apoptotic deregulation of endothelial cells and intimal proliferation in pulmonary hypertension of congenital heart disease].
abstract: OBJECTIVE
  To assess the cellular and histological basis of irreversible pulmonary hypertension (PHT) in the clinical setting of congenital heart disease (CHD).
  
  
  BACKGROUND
  Although many children with CHD develop pulmonary vascular disease, it is unclear why this complication is reversible after complete repair in some cases but irreversible in others. As failure of endothelial cell apoptosis might lead to intimal proliferation and lack of reversibility of PHT, we investigated this and other key markers of vasoactivity and angiogenesis, in subjects with PHT and CHD.
  
  
  METHODS
  We assessed anti- and pro-apoptotic markers in vascular and perivascular cells in lung biopsies from 18 patients with CHD; 7 with reversible and 11 with irreversible PHT, and from 6 controls. Immunostaining for eNOS, VEGF and CD34 (markers of vasoactivity and neoangiogenesis) was also performed.
  
  
  RESULTS
  The anti-apoptotic protein Bcl-2 was highly expressed by pulmonary endothelial cells in all cases of irreversible PHT but in no cases of reversible PHT, nor in controls (p<0.001). Intimal proliferation was present in 10/11 irreversible PHT cases but never observed in reversible PHT (p<0.001). Similarly, perivascular inflammatory T-cells expressed more anti-apoptotic proteins in irreversible PHT (p<0.01). Irreversible PHT cases were also more likely to show compensatory up-regulation of VEGF and new small vessel formation at the sites of native vessel stenosis or occlusion (p<0.001).
  
  
  CONCLUSIONS
  Irreversible PHT is strongly associated with impaired endothelial cell apoptosis and anti-apoptotic signalling from perivascular inflammatory cells. These changes are associated with intimal proliferation and vessel narrowing and thereby may contribute to clinical outcomes associated with pulmonary hypertension. Markers of apoptosis and angiogenesis were assessed in lung biopsies of subjects with pulmonary hypertension (PHT) due to congenital heart disease (CHD). The anti-apoptotic protein Bcl-2 was strongly expressed by pulmonary endothelial cells in irreversible PHT (n=11) but never in reversible PHT (n=7) (p<0.01). Irreversible PHT was also associated with up-regulation of VEGF and new vessel formation around occluded native vessels (p<0.01).
authors.affiliation: UPRES EA4068, UFR Biomédicale des Saints-Pères et Faculté de médecine, Paris V.
authors.forename: M
authors.initials: M
authors.lastname: Lévy
authors.forename: O
authors.initials: O
authors.lastname: Raisky
authors.forename: P-R
authors.initials: PR
authors.lastname: Vouhé
authors.forename: D-S
authors.initials: DS
authors.lastname: Celermajer
authors.forename: D
authors.initials: D
authors.lastname: Bonnet
authors.forename: D
authors.initials: D
authors.lastname: Israël-Biet
mesh_terms: D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000032:analysis; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006330:Heart Defects, Congenital / Q000150:complications* / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology*; D007223:Infant; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000473:pathology; D017539:Tunica Intima / Q000473:pathology* / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers; D019253:Proto-Oncogene Proteins c-bcl-2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III