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(Chest. 2002;121:61S.)
© 2002 American College of Chest Physicians

Microsatellite Mutational Analysis of Endothelial Cells Within Plexiform Lesions From Patients With Familial, Pediatric, and Sporadic Pulmonary Hypertension*

Michael E. Yeager, BS; Heiko. A. Golpon, MD; Norbert F. Voelkel, MD and Rubin M. Tuder, MD

* From the Pulmonary Hypertension Center, Division of Pulmonary Sciences, Departments of Medicine and Pathology, University of Colorado Health Sciences Center, Denver CO.

Correspondence to: Michael E. Yeager, BS, Graduate Student, Department of Pathology, University of Colorado Health Sciences Center, Box B216, 4200 E. 9th Ave, Denver, CO 80262; e-mail: mike.yeager{at}uchsc.edu

Severe pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressures leading to right-heart failure, yet the pathogeneses of familial PH, pediatric PH, and sporadic PH (SPH) are poorly understood. We previously demonstrated monoclonal proliferation of endothelial cells (ECs) within plexiform lesions in primary SPH, and we showed that plexiform ECs display dysregulated gene expression compared to normal pulmonary ECs arranged in monolayers. We posited that mutations in genes controlling EC growth and death might drive monoclonal EC growth in plexiform lesions. Using polymerase chain reaction, we found microsatellite instability within the hMSH2 mismatch repair gene and frameshift mutation within the transforming growth factor-ß receptor type II (TGF-ß RII) and Bax genes. Specifically, we show genetic instability in 13 patients with primary SPH (6 of 19 lesions TGF-ß RII; 4 of 19 lesions Bax) and in 1 patient with primary pediatric PH (2 of 5 lesions hMSH2), but not in 5 patients with familial PH (0 of 16 lesions) nor in 10 normal lungs. EC monoclonality, when performed, correlated tightly with occurrence of mutation (three of three primary SPH patients). Immunohistochemistry revealed absence of TGF-ß RII, hMSH2, and hMLH1 expression in plexiform lesion ECs of SPH tissues compared to ECs in normal pulmonary arteries from both normal and PH patients. To our knowledge, this is the first report of mutation within ECs outside the setting of neoplasia. Our observations may assist in subclassification of PH patients as well as point to future novel therapeutic interventions.


   Footnotes
 
Abbreviations: EC = endothelial cell; PH = pulmonary hypertension; SPH = sporadic pulmonary hypertension; TGF-ß RII = transforming growth factor-ß receptor type II




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