The role of oxidative stress in the development of pulmonary arteriovenous malformations after cavopulmonary anastomosis.
BACKGROUND
Cavopulmonary anastomosis is used for palliation of cyanotic heart disease. Clinically significant pulmonary arteriovenous malformations occur in up to 25% of patients after surgical intervention. Cavopulmonary anastomosis creates several modifications to pulmonary physiology that may contribute to the development of pulmonary arteriovenous malformations, including reduced pulmonary blood flow and the exclusion of inferior vena caval effluent.


OBJECTIVE
By comparing the expression of angiogenic and stress-related proteins after cavopulmonary anastomosis and pulmonary artery banding, we sought to determine which genes were upregulated independent of reduced pulmonary blood flow.


METHODS
Lambs aged 35 to 45 days were placed into 1 of 3 groups: cavopulmonary anastomosis (n = 6), pulmonary artery banding (n = 6), and sham control (n = 6) animals. In our model pulmonary arteriovenous malformations are detectable by means of bubble-contrast echocardiography 8 weeks after cavopulmonary anastomosis. Lung tissue was harvested for Western blotting at 2 and 5 weeks after surgery.


RESULTS
Cavopulmonary anastomosis and pulmonary artery banding both increased angiogenic gene expression, but only cavopulmonary anastomosis induced the expression of endothelial stress-related genes. Vascular endothelial growth factor was upregulated 2.5-fold after both cavopulmonary anastomosis (P =.002) and pulmonary artery banding (P =.007). Only cavopulmonary anastomosis upregulated 2 stress-related genes, HO1 and GLUT1, 2.7-fold (P =.002) and 3.8-fold (P =.03), respectively. Hypoxia-inducible factor was upregulated 4-fold (P =.003) after cavopulmonary anastomosis. Pulmonary artery banding failed to induce the increased expression of any of these proteins.


CONCLUSIONS
Reduced pulmonary blood flow induces a pulmonary angiogenic response but not an endothelial stress response. These results suggest that oxidative stress is more relevant to the formation of pulmonary arteriovenous malformations than angiogenic signaling alone because pulmonary artery banding does not result in pulmonary arteriovenous malformations. Oxidative stress of the pulmonary endothelium resulting from cavopulmonary anastomosis may predispose the affected vasculature to arteriovenous shunting.
Malhotra
Sunil P
SP
Division of Cardiothoracic Surgery, University of California, San Francisco, Calif. 94305-5407, USA.
Reddy
V Mohan
VM
Thelitz
Stephan
S
He
You-Ping
YP
McMullan
D Michael
DM
Hanley
Frank L
FL
Riemer
R Kirk
RK
D000818:Animals; D001165:Arteriovenous Malformations / Q000235:genetics* / Q000601:surgery*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D051272:Glucose Transporter Type 1; D018610:Heart Bypass, Right; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008168:Lung / Q000098:blood supply*; D008222:Lymphokines / Q000235:genetics / Q000276:immunology; D008955:Models, Cardiovascular; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology*; D019007:P-Selectin / Q000235:genetics / Q000276:immunology; D011651:Pulmonary Artery / Q000002:abnormalities* / Q000601:surgery*; D011667:Pulmonary Veins / Q000002:abnormalities* / Q000601:surgery*; D012756:Sheep; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005819:Genetic Markers; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009004:Monosaccharide Transport Proteins; D019007:P-Selectin; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1