Protein kinase Bα/Akt1 regulates placental development and fetal growth

Protein kinase Balpha (PKBalpha/Akt1) is implicated in the regulation of metabolism, transcription, cell survival, angiogenesis, cell migration, growth, and tumorigenesis. Previously, it was reported that PKBalpha-deficient mice are small with increased neonatal mortality (Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F., and Birnbaum, M. J. ( 2001) J. Biol. Chem. 276, 38349 - 38352 and Chen, W. S., Xu, P. Z., Gottlob, K., Chen, M. L., Sokol, K., Shiyanova, T., Roninson, I., Wenig, W., Suzuki, R., Tobe, K., Kadowaki, T., and Hay, N. ( 2001) Genes Dev. 15, 2203 2208). Here we show that PKBalpha is widely expressed in placenta including all types of trophoblast and vascular endothelial cells. Pkbalpha(-/-) placentae display significant hypotrophy, with marked reduction of the decidual basalis and nearly complete loss of glycogen-containing cells in the spongiotrophoblast, and exhibit decreased vascularization. Pkbalpha(-/-) placentae also show significant reduction of phosphorylation of PKB and endothelial nitric-oxide synthase. These defects may cause placental insufficiency, fetal growth impairment, and neonatal mortality. These data represent the first evidence for the role of PKBalpha and endothelial nitric-oxide synthase in regulating placental development and provide an animal model for intrauterine growth retardation.