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Ann Thorac Surg 2004;77:463
© 2004 The Society of Thoracic Surgeons
Department of Cardiac Surgery, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA
e-mail: pedro.delnido{at}tch.harvard.edu
e-mail: ingeborg.friehs{at}tch.harvard.edu
In the present study, the authors tested the efficacy of adenoviral mediated gene transfer of VEGF165 to a single lung pulmonary artery stenosis model in fetal lambs, with the treatment being given early postnatally. The authors' choice of a pulmonary artery stenosis model makes the present study relevant to the clinical situation of tetralogy of Fallot and severe pulmonary stenosis or atresia. Their findings indicate that central pulmonary artery growth does occur in response to VEGF treatment and may have potential therapeutic benefit for children.
In patients with pulmonary atresia and tetralogy of Fallot, the intrapulmonary arterial circulation usually fails to grow and develop normally as pulmonary blood flow is abnormally low before birth [1]. Both preacinar and intraacinar arteries are small, thin-walled, and relatively nonmuscular; and the total number may be reduced. Vessel development in the lung is a continuous process that begins at the earliest stages of fetal development, making the pulmonary vasculature vulnerable to perturbation in utero and postnatally [2]. The expression of VEGF coordinates development of alveolarization and vascular growth pre and post-natally, which is essential for normal lung development [3]. Thus conceptually, VEGF expression seems an excellent target for manipulation in an effort to promote coordinated lung development in children with pulmonary atresia.
In the present study, however, a few unanswered questions remain. The finding that the volume of the banded lung was substantially reduced is at variance with results of other investigators using similar banding models and what is observed clinically. Furthermore, promoting angiogenesis with VEGF did not result in an increase in lung volume as compared with control-banded and beta-gal-treated animals, indicating that VEGF did not contribute to an increase in lung growth in this model. Thus it appears that VEGF overexpression in this model had a proangiogenic effect without parenchymal growth, which is also at variance with its proposed role in normal lung development.
To further explore the findings of the present study, it is important to remember that the normal lung is a highly vascular structure, which makes detecting newly formed blood vessels extremely difficult. Ideally, formation of new capillary blood vessels in the lung after VEGF treatment should be evaluated by both histologic and functional measures. In particular, special emphasis should be placed on detecting the presence of histologic and functional abnormalities in vascular structure such as pulmonary arteriovenous fistulae which can result in a significant intrapulmonary shunt. Indeed, VEGF has been implicated in the etiology of A–V fistulae formation in patients with a surgically created cavo-pulmonary connection, also called the Glenn shunt [4].
In this study, the authors offer an interesting potential solution to a problem often seen in the pulmonary vasculature of children and adults with pulmonary atresia. If angiogenesis could be achieved in a coordinated manner with alveolae, operative morbidity and mortality as well as the long-term outlook for this difficult group of patients would likely be substantially improved. However, further insight is needed into the proangiogenic effects of VEGF overexpression in the lung before clinical application is contemplated.
References
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