Imaging angiogenesis in the lung

Angiogenesis refers to the process by which new blood vessels form to meet new needs demanded by ischemic tissue. In several pathologic processes, angiogenesis arises as a response to specific insults. For instance, when lung tumors grow beyond the point at which they can be nourished by the existing pulmonary circulation, the cancerous tissue becomes ischemic and starts signaling a need for increased perfusion. Without such increased perfusion, tumor growth could not continue, and this is the motivation for the intensive search for inhibitors of angiogenesis as a therapy for cancer. In chronic asthma, there is often a slight thickening of the airway wall, accompanied by increased smooth muscle and vascularization. These new blood vessels may contribute to the warming or humidification of inspired air, but their precise role in this disease remains somewhat controversial (1). Angiogenesis in the lung also occurs where there is pathologic obstruction of the pulmonary vasculature. In such cases, the bronchial circulation expands to meet the needs of the ischemic tissue. Although this process is clearly beneficial in keeping the lung tissue alive, the gas exchange function of the lung is not corrected. Although hypoxia is often listed as a stimulus for angiogenesis, the fact that angiogenesis readily occurs in the ventilated lung with obstruction of deoxygenated pulmonary blood flow proves that ischemia is the more relevant stimulus. Because these new vessels to ischemic tissue always originate from the microcirculation, attempts to visualize such vessels will clearly stress the limits of all imaging modalities. In a recent excellent review article, the applications and limitations of many of these techniques in systemic organs are described (2). However, the lung poses unique challenges because efforts to visualize angiogenesis in this organ are hampered by several physiological factors. Most significant is the fact that new vessel growth predominantly arises from the systemic circulation that normally perfuses the airways and thorax. Although changes in pulmonary vessels occasionally appear in metastases (3), nearly all observations of lung angiogenesis can trace the origin of new vessels to their arterial sources from either the tracheobronchial vasculature or intercostal arteries surrounding the lungs. Although in animal models this neovascularization can develop to as much as 30% of the cardiac output (4), under normal conditions the bronchial circulation represents, 3% of cardiac output (5). Because of the two distinct vascular systems within the lungs, the larger and recruitable pulmonary vasculature obscure small angiogenic alterations of the bronchial vasculature. In vivo imaging of the lungs with bronchial arteriograms can provide qualitative information about neovascularization. However, to confirm new vessel proliferation, investigators have resorted to histologic evaluation of tissue biopsy specimens with quantification of vascular density. Even this approach has been difficult because unique endothelial markers distinguishing new angiogenic vessels relative to pulmonary vessels are not currently apparent, although a few studies have focused on defining endothelial heterogeneity within normal lungs (6,7). Thus, in vivo imaging of neovascularization within the lungs represents a significant challenge requiring further characterization of vascular phenotype. This chapter is organized around three different but well-characterized pathophysiologic conditions, for which different imaging modalities are being used to assess vascular function and angiogenesis: asthma, pulmonary artery obstruction, and lung cancer.