Gene array analysis of a rat model of pulmonary arteriovenous malformations after superior cavopulmonary anastomosis
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Published on: February 11, 2017
Russell S Tipps1, Muhammed Mumtaz, Patrick Leahy
1Department of Pediatric and Congenital Heart Surgery, Children's Hospital, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Insights
Pulmonary arteriovenous malformations after cavopulmonary anastomosis in rats show altered gene expression. These changes in angiogenesis, vascular remodeling, and vasoactive genes may cause the condition.
Area of Science:
- Cardiovascular Research
- Pediatric Surgery
- Molecular Biology
Background:
- Pulmonary arteriovenous malformations (PAVMs) frequently occur in children post-cavopulmonary anastomosis for single-ventricle physiology.
- Understanding the molecular mechanisms behind PAVM development is crucial for improving pediatric cardiac surgical outcomes.
Purpose of the Study:
- To establish a rat model mimicking human PAVMs post-cavopulmonary anastomosis.
- To investigate the gene expression profile associated with PAVM development in this model.
Main Methods:
- A rat model of right superior cavopulmonary anastomosis was created, with the contralateral lung serving as a control.
- Gene expression profiling was performed using Affymetrix Rat Microarray RAE230 2.0.
- Analysis focused on identifying differentially expressed genes between operated and control lungs.
Main Results:
- 137 genes showed altered expression in lungs post-cavopulmonary anastomosis.
- Key modulated genes were involved in angiogenesis (e.g., angiopoietin-2, placental growth factor), vascular remodeling (e.g., matrix metalloproteases, collagens), and vasoactive properties (e.g., endothelin 1).
- Transforming growth factor beta superfamily signaling pathway genes were also affected.
Conclusions:
- The observed gene expression changes suggest a potential causative role in PAVM development following cavopulmonary anastomosis.
- This rat model provides a valuable tool for studying PAVM pathogenesis and exploring therapeutic targets.
Objective:
Pulmonary arteriovenous malformations commonly develop in children who have undergone a cavopulmonary anastomosis as part of the palliative sequence for single-ventricle physiology.
Methods:
We developed a rat model of cavopulmonary anastomosis that results in pulmonary arteriovenous malformations that are angiographically and histologically similar to the human condition. We used this model to analyze the gene expression profile associated with pulmonary arteriovenous malformations developing after cavopulmonary anastomosis.
Results:
Six Sprague-Dawley rats underwent right superior cavopulmonary anastomosis, allowing the left lung to serve as a control. Total RNA was isolated from each lung at death 8 months postoperatively and compared by using the Affymetrix Rat Microarray RAE230 2.0 GeneChip (Affymetrix, Santa Clara, Calif). One hundred thirty-seven genes demonstrated altered expression in the lungs after cavopulmonary anastomosis compared with that seen in the control lungs: 55 (40%) genes demonstrated increased expression, and 82 (60%) genes demonstrated decreased expression. Modulation of genes associated with angiogenesis and vascular remodeling was found, including angiopoietin-2, placental growth factor, several matrix metalloproteases, and several collagen subtypes. Genes with vasoactive properties, including endothelin 1 and endothelin receptor type B, demonstrated altered gene expression. Several members of the transforming growth factor beta superfamily signaling pathway also demonstrated altered expression.
Conclusions:
These changes in gene expression might have causative implications for pulmonary arteriovenous malformations that develop after cavopulmonary anastomosis.
