Brian W. Duncan1, Russell S. Tipps1, Patrick Leahy2, Muhammad A. Mumtaz1; 1Pediatric and Congenital Heart Surgery, Children's Hospital, Cleveland Clinic, Cleveland, OH; 2Comprehensive Cancer Center, Case Western Reserve University School of Medicine and University Hospital, Cleveland, OH
Objective: Pulmonary arteriovenous malformations (PAVMs) commonly develop in children who have undergone a cavopulmonary anastomosis (CPA) as part of the operative sequence for palliation of single ventricle physiology. We previously developed a rat model of experimental CPA in rats that results in PAVMs that appear to be angiographically and histologically similar to the human condition. In the present study, we utilized this rat model to analyze the gene expression profile associated with the development of PAVMs after CPA.Methods: Six male Sprague-Dawley rats (200-300 gms) underwent a unilateral, right superior CPA allowing the left lung to serve as a control. Total RNA was isolated from the right (CPA) and left (control) lungs from each animal at the time of sacrifice 8-9 months post-operatively and compared using the Affymetrix Rat Microarray RAE230 2.0 GeneChip.
Results: Cavopulmonary anastomosis resulted in modulation of a number of genes associated with angiogenesis and/or vascular remodeling including angiopoietin 2, placental growth factor, insulin-like growth factors 3 and 5, cadherin 13, endothelial cell-specific molecule-1, integrin-β4, interleukin-1β, tissue plasminogen activator, several matrix metalloproteases and several collagen subtypes. In addition, significant alterations in expression of several genes associated with changes in or maintenance of vascular tone were observed including neuropeptide Y, endothelin-1 and endothelin receptor type B. Finally, several members of the TGF-β superfamily signaling pathway were also substantially modulated in the CPA lungs compared to controls.
Conclusion: 1) There is altered expression of a number of genes associated with a wide range of functions including angiogenesis, vascular remodeling and maintenance of vascular tone in the lungs following CPA. 2) Histologically, PAVMs that develop after CPA are characterized by the presence of large numbers of abnormally dilated, thin-walled blood vessels that extend far into the periphery of the lung. 3) The differential gene expression demonstrated in the lungs of this rat model following CPA involving angiogenesis, vascular remodeling and vascular tone may have etiologic implications for the development of PAVMs in this clinical setting.
Back to Annual Meeting
Back to Program Outline
