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INVITED EDITORIAL
Laboratoire de Chirurgie Expérimentale UPRES-EA 2705, Paris South University, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
Laboratoire de Chirurgie Expérimentale UPRES-EA
Paris South University
Hôpital Marie Lannelongue
Le Plessis-Robinson, France
e-mail: pherve{at}ccml.fr
Five hundred years ago, Leonardo da Vinci demonstrated that new bronchial vessels can develop in a human lung. The development of a mouse model of pulmonary artery obstruction in recent years (1) has provided substantial insight into the mechanisms and consequences of the systemic neovascularization of the lung.
In the mouse, new vessels grow exclusively from intercostal arteries, bridging the pleural space and perfusing the lung, and not from the poorly developed bronchial vasculature. This feature may explain why, after pulmonary artery occlusion in this animal, systemic blood flow to the occluded lung reaches only a maximum of 
6% of the cardiac output, whereas in other species or in patients with chronic thromboembolic pulmonary hypertension it may achieve up to 30% of the cardiac output (it is <3% in normal subjects) (2).
It is not clear whether these new systemic vascular networks are truly developing (vasculogenesis) or whether preexisting vessels are remodeling to accommodate perfusion from the new systemic source (angiogenesis and arteriogenesis). Vasculogenesis results from the differentiation of circulating bone marrow-derived endothelial progenitor cells into mature endothelial cells and contribute to neovascularization after ischemia (3). On the other hand, angiogenesis involves the remodeling of an established capillary network to generate new capillaries, and arteriogenesis consists in the development of collateral arteries from preexisting arteriolar connections (3). Whereas angiogenesis is mainly observed in peripheral ischemic territories, arteriogenesis is temporally and spatially dissociated from ischemia (3). Angiogenesis and vasculogenesis rely on ischemia-induced angiogenic factors such as VEGF, whereas arteriogenesis is triggered by physical forces, such as fluid shear stress, and by monocyte-macrophage-related vascular remodeling (3). When a pulmonary artery is occluded, the lung most likely requires both angiogenesis to connect the systemic circulation with the ischemic pulmonary microcirculation and arteriogenesis to increase systemic source of pulmonary anastomotic blood flow.
Whether ischemia increases VEGF in the lung as in peripheral tissues is controversial. It was previously found in ferret (4), pig (S. Eddahibi, personal communication), and mice (5) that VEGF mRNA and protein increase early after a left pulmonary artery obstruction, thus suggesting that this factor plays a role in the early angiogenesis response to pulmonary ischemia. However, when lung sample harvesting was subsequently done more carefully in mice, measuring upper left lung (proangiogenic) vs. lower left lung (ischemic without angiogenesis), there was no difference in the VEGF signal (6). Subsequent studies in mice have suggested that the VEGF signal was associated with intravascular neutrophils (7) and that these cells do not contribute to the angiogenic response (8). A recent study (6) used the oligonucleotide microarray to study early expression of those genes responsible for the initiation of systemic vascular proliferation after pulmonary artery ligation. Two interleukin genes (IL-6, IL-1), three CXC chemokines (macrophage inflammatory protein-2, keratinocyte-derived chemokine, and lipopolysaccharide-inducible CXC chemokine), and two genes specifically expressed in macrophages (MARCO and ADAM8) were increased within 24 h after left pulmonary artery ligation. The histological demonstration of an increase in the number of macrophages in the occluded mice lung (9) is consistent with this observation and with previous findings in the lungs from patients with chronic thromboembolic pulmonary obstruction (10). It is most likely that macrophages play a central role in tissue remodeling and vessel recruitment to the ischemic lung, as demonstrated in other systemic vascular beds (3).
Although the stimulus for vascular proliferation must originate in the ischemic microvasculature, the remodeling extends to the large bronchial vessels. The mechanisms probably involve both hemodynamic and nonhemodynamic factors. Interruption of the pulmonary blood flow increases the driving forces across preexisting systemic-to-pulmonary anastomoses, leading to gradual increases in systemic-to-pulmonary blood flow, bronchial artery wall shear stress, and bronchial artery lumen diameter. A temporal relationship should also exist between peripheral angiogenesis and arteriogenesis (3). The angiogenic component with the development of bronchopulmonary anastomoses likely precedes the arteriogenic component with the formation of a collateral vasculature. VEGF may be responsible for mediating the immediate-early angiogenic response, whereas chemokines may facilitate the recruitment of macrophages for the mid-to-late arteriogenic response (3).
Hyperplasia of the pulmonary artery vasa vasorum constitutes another important systemic angiogenic response to pulmonary artery obstruction. In patients with chronic thromboembolic obstruction of the pulmonary arteries, the number of pulmonary adventitial vasa vasorum increases and the core of the nonresolving clots is recanalized by neovascular endothelialized structures that originate from the vasa vasorum (10). Because the walls of the obstructed pulmonary artery are infiltrated by numerous macrophages, we speculate that these cells stimulate proliferation of the vasa vasorum, allowing further delivery of bone marrow-derived endothelial progenitor cells for local vasculogenesis within the fibrotic matrix of the nonresolving clots.
Systemic neovascularization to the occluded lung is obviously an important adaptive process to maintain the viability of pulmonary tissues. However, despite the relative conservation of the pulmonary aerobic metabolism, prolonged lung ischemia damages the pulmonary endothelium. As a result, lung permeability increases, as reported by Wagner et al. in this issue of the Journal (11). Preliminary data from our laboratory demonstrate the presence of 20% of apoptotic cells in the distal ischemic pulmonary endothelium (E. Fadel and S. Eddahibi, personal communication) and suggest that this increase in lung permeability may be related to an alteration in the endothelial cytoskeleton. The decrease in nitric oxide production by the pulmonary endothelium, as recently reported after chronic lung ischemia (12), might also be involved because constitutive endothelial nitric oxide synthesis in pulmonary endothelium is critical to establishing barrier properties within the lung. Alternatively, the systemic neovascularization may contribute to the regeneration of injured pulmonary endothelium by providing bone marrow-derived endothelial progenitor cells to compensate for the endothelial cells death.
Another consequence of the systemic neovascularization of the lung is the risk of massive hemoptysis. Interestingly, hemoptysis has not been reported after pulmonary thromboendarterectomy has allowed reperfusion of pulmonary arteries previously occluded by chronic organized thrombi. This suggests that systemic-to-pulmonary vascularization may decrease when circulation in the pulmonary bed is restored. Indeed, we have recently demonstrated in pigs that restoring the pulmonary circulation after a period of pulmonary artery occlusion normalizes the systemic collateral blood flow to the reperfused lung and leads to anatomic involution of the newly formed collateral vessels (13). Such vascular responses reflect the plasticity of the bronchial circulation.
Knowledge about the systemic neovascularization of the lung has steadily progressed since Leonardo's time, and the interplay of physical forces with cellular and molecular mechanisms is now better known. However, many aspects of this vascular remodeling remain to be understood.
REFERENCES
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