Akt/Protein Kinase B Is Required for Lymphatic Network Formation, Remodeling, and Valve Development

Akt-mediated signaling plays an important role in blood vascular development. In this study, we investigated the role of Akt in lymphatic growth using Akt-deficient mice. First, we found that lymphangiogenesis occurred in Akt1−/−, Akt2−/−, and Akt3−/− mice. However, both the diameter and endothelial cell number of lymphatic capillaries were significantly less in Akt1−/− mice than in wild-type control mice, whereas there was only a slight change in Akt2−/− and Akt3−/− mice. Second, valves present in the small collecting lymphatics in the superficial dermal layer of the ear skin were rarely observed in Akt1−/− mice, although these valves could be detected in the large collecting lymphatics in the deep layer of the skin tissues. A fluorescence microlymphangiography assay showed that the skin lymphatic network in Akt1−/− mice was functional but abnormal as shown by fluorescein isothiocyanate-dextran draining. There was an uncharacteristic enlargement of collecting lymphatic vessels, and further analysis showed that smooth muscle cell coverage of collecting lymphatic vessels became much more sparse in Akt1-deficient mice than in wild-type control animals. Finally, we showed that lymphatic vessels were detected in compound Akt-null mice and that lymphangiogenesis could be induced by vascular endothelial growth factor-C delivered via adenoviral vectors in adult mice lacking Akt1. These results indicate that despite the compensatory roles of other Akt isoforms, Akt1 is more critically required during lymphatic development.