Although several molecular players have been described that play a role during the early phases of lung development, it is still unknown how the vasculature develops in relation to the airways. Two opposing models describe development of lung vasculature: one suggests that both vasculogenesis and angiogenesis are involved, whereas the second describes vasculogenesis as the primary mechanism. Therefore, we examined the development of the murine pulmonary vasculature through a morphological analysis from the onset of lung development [9.5 days postcoital (dpc)] until the pseudoglandular stage (13.5 dpc). We analyzed fetal lungs of Tie2-LacZ transgenic mice as well as serial sections of wild-type lungs stained with endothelial-specific antibodies (Flk-1, Fli-1, and PECAM-1). Embryos were processed with intact blood circulation to maintain the integrity of the vasculature; hence individual vessels could be identified with accuracy through serial section analysis. Furthermore, circulating primitive erythrocytes, formed exclusively by the blood islands in the yolk sac, are trapped in vessels during fixation, which proves the connection with the embryonic circulation. We report that from the first morphological sign of lung development, a clear vascular network exists that is in contact with the embryonic circulation. We propose distal angiogenesis as a new concept for early pulmonary vascular morphogenesis. In this model, capillary networks surround the terminal buds and expand by formation of new capillaries from preexisting vessels as the lung bud grows. The fact that at an early embryonic stage a complete vascular network exists may be important for the general understanding of embryonic development. mouse; bronchial and pulmonary system THE ADULT LUNG has a dual vascular system, the bronchial and the pulmonary system. The bronchial system oxygenates all nonrespiratory structures of the lung, whereas the pulmonary system transports deoxygenated blood to the alveoli for gas exchange. The pulmonary arteries arise from the pulmonary trunk of the heart and closely follow the bronchial tree, giving rise to the alveolar capillary plexus. These capillaries drain into the pulmonary veins, which run through the connective tissue septa back to the left atrium of the heart. Type I alveolar cells and endothelial cells form an air-blood barrier, which is mandatory for optimal gas exchange. Abnormalities in this delicate architecture may lead to inadequate function, as presented in congenital anomalies of the lung, such as congenital diaphragmatic hernia (32) and alveolar capillary dysplasia (1). The intimate anatomical structure suggests that the close interaction between the pulmonary vessels and the airways starts to be established early in development. However, the process by which the pulmonary vascular tree develops and the factors that control pulmonary vascular development are not completely understood.Lung development is divided into distinctive stages with the earliest stages consisting of the embryonic stage, embryoni...

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