title: Regression of flow-induced pulmonary arterial vasculopathy after flow correction in piglets.
abstract: OBJECTIVE
  Chronic thromboembolic pulmonary hypertension is due to partial obstruction of the pulmonary arterial bed and may resolve after pulmonary thromboendarterectomy. Persistent pulmonary hypertension, the main complication after pulmonary thromboendarterectomy, may reflect vessel alterations induced by high flow in unobstructed lung territories. The aim of this study was to determine whether correcting high flow led to reversal of the vasculopathy in piglets.
  
  
  METHODS
  The effects of high pulmonary blood flow were investigated 5 weeks after creation of an aortopulmonary shunt (n = 10), and reversibility of vessel disease was evaluated at 1 week (n = 10) and 5 weeks after shunt closure (n = 10), compared to sham-operated animals (n = 10). Hemodynamic variables, pulmonary artery reactivity, and morphometry were recorded. We also investigated the endothelin, angiopoietin, and nitric oxide synthase pathways.
  
  
  RESULTS
  High flow increased medial thickness in distal pulmonary arteries (55.6% +/- 1.2% vs 35.9% +/- 0.8%; P < .0001) owing to an increase of smooth muscle cell proliferation (proliferating cell nuclear antigen labeling). The endothelium-dependent relaxation was altered (P < .05). This phenomenon was associated to an overexpression of endothelin-1, endothelin-A, angiopoietin 1, angiopoietin 2, and Tie-2 (P < .05). After 1 week of shunt closure, all overexpressed genes returned to control values, the proliferation of smooth muscle cells stopped, and smooth muscle cell apoptosis increased (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), preceding the normalization of the wall thickness hypertrophy and the pulmonary artery vasoreactivity observed at 5 weeks after shunt closure.
  
  
  CONCLUSIONS
  These results demonstrate that endothelin-1 and angiopoietin pathways are involved in vasculopathy development and may be important therapeutic targets for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.
authors.affiliation: Laboratoire de Chirurgie Expérimentale UPRES-EA 2705, Uninersité Paris XI Hôpital Marie Lannelongue, Le Plessis-Robinson, France. o.mercier@ccml.fr
authors.forename: Olaf
authors.initials: O
authors.lastname: Mercier
authors.forename: Edouard
authors.initials: E
authors.lastname: Sage
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
authors.forename: Ly
authors.initials: L
authors.lastname: Tu
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Marcos
authors.forename: Benoît
authors.initials: B
authors.lastname: Decante
authors.forename: Bruno
authors.initials: B
authors.lastname: Baudet
authors.forename: Philippe
authors.initials: P
authors.lastname: Hervé
authors.forename: Philippe
authors.initials: P
authors.lastname: Dartevelle
authors.forename: Saadia
authors.initials: S
authors.lastname: Eddahibi
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004691:Endarterectomy; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011652:Pulmonary Circulation; D011655:Pulmonary Embolism / Q000150:complications / Q000601:surgery*; D042787:Receptor, TIE-2 / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D017540:Tunica Media / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D042683:Angiopoietin-1; D019332:Endothelin-1; D017466:Receptors, Endothelin; D003094:Collagen; D019001:Nitric Oxide Synthase; D042787:Receptor, TIE-2; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D000109:Acetylcholine