Ann Thorac Surg 2004;77:456-457
© 2004 The Society of Thoracic Surgeons
Invited commentary
Vibeke Videm, MD, PhD
Department of Immunology and Transfusion Medicine, Institute of Laboratory Medicine, Children's and Women's Health, Trondheim University Hospital, Norwegian University of Science and Technology, N-7006 Trondheim, Norway
e-mail: vibeke.videm{at}medisin.ntnu.no
Pulmonary hypertension is a debilitating disease associated with disparate factors, ranging from pulmonary disorders, thromboembolism, and familial genetic aberrations to the use of appetite suppressants. The exact mechanisms of the disease remain unknown, and might vary for different forms. A more general hypothesis is evolving, however, and the present paper by Dr Chu and coworkers from Dr Thistlethwaite's group provides significant support for it.
The vascular endothelial growth factor (VEGF) family and angiopoietin family of growth factors are known to act in concert on the blood vasculature. The VEGFs initiate vessel growth, whereas the angiopoietins seem to promote vessel maturation and maintenance. Angiopoietin-1 acts through the receptor tyrosine kinase Tie2. Previous work from the same group has linked this signaling pathway to the bone morphogenic protein receptor (BMPR) family. In addition to affecting bone growth, these receptors are involved in regulation of smooth muscle proliferation. The family includes a primary gene for inherited pulmonary hypertension, named BMPR2. Since angiopoietin-1 downregulates the BMP pathway, overexpression may lead to the same dysregulation of vascular smooth muscle cell inhibition as seen with BMPR2 mutations in the familial forms of the disease. The result is increased proliferation of smooth muscle cells and obstruction of small pulmonary vessels.
The present paper employs gene transfer methods allowing local angiopoietin-1 overexpression in the pulmonary vasculature of adult rats. This model probably comes closer to the clinical situation than the traditional method that uses intraperitoneal injection of monocrotaline to induce pulmonary hypertension. As predicted by their hypothesis, the authors showed that the rats developed clinical and pathological changes consistent with advanced pulmonary hypertension, which was unrelated to the gene transfer technique itself. The paper very nicely demonstrates hypertrophy/hyperplasia of the media of pulmonary vessels following angiopoietin-1 overexpression. However, a number of publications on different forms of pulmonary hypertension in humans indicate remodeling of all layers of the vessel wall. Compared to the clinical disease, the rats also showed fewer plexiform lesions, which are regarded as a classic pathological finding. These observations may indicate that other genes are also involved in the ethiology of pulmonary hypertension. In any case, the present paper adds important knowledge that should certainly inspire future efforts to establish a more detailed understanding of the molecular basis of this disease.
