Abstract 1910: Expression Profiling of Thoracic Vessels Reveals That Aorto-Pulmonary Collaterals Are Distinctly Different From Contiguous Vessels
Major Aorto-Pulmonary Collateral Arteries (MAPCA) complicate a subset of pediatric cardiac patients with Tetralogy of Fallot (TOF) and present substantial clinical and surgical management challenges. Complex surgical operations utilizing MAPCAs as raw material for reconstruction of pulmonary arteries are needed to reestablish the normal pulmonary flow connection. A major clinical problem is the propensity of MAPCAs toward developing stenosis rather than the expected progressive growth. We have initiated studies comparing gene expression profiles of MAPCAs with those of neighboring contiguous vessels to further understand their basic biology.
Methods: Specimens were analyzed from MAPCA (n=10), pulmonary artery (PA, n=10); and aorta (Ao, n=4) of patients undergoing repair for TOF or Transposition of Great Arteries, respectively. RNA extracts from 3 MAPCA & PA pairs from 3 patients, and Ao specimens from 3 other patients were first analyzed using 9 Affymetrix U133-PLUS-2 Human Genome arrays. Relative mRNA expression array values were confirmed in additional specimens using TaqMan quantitative PCR.
Results: Significant differences in mRNA expression level (p<0.01) were observed for multiple genes comprising several classes. Compared with either Aorta (Ao) or Pulmonary artery (PA), MAPCAs differentially express many genes at much higher levels. For example, MAPCAs expressed >26× higher levels of the cytoskeletal and transcriptional regulator FHL5, >14× higher levels of the calcium binding protein CASQ, and 5× higher levels of the membrane fusion and transcriptional regulatory protein SLP2. Expression of the BMP antagonist protein gene GREM2 was 8× lower in MAPCAs.
Conclusion: MAPCAs can be differentiated from PA and Ao by markedly altered levels in expression of multiple genes of varied function. The distinctly different gene expression pattern of MAPCAs may underlie their unusual behavior. Knowledge about the basic biology of MAPCAs obtained through further studies of the roles of the differentially expressed genes in their vascular physiology may enable novel therapeutic approaches for improving the surgical outcomes for MAPCA patients. Understanding these expression differences may also help to decipher the complex genetics of TOF.