Gao, F., Artham, S., Sabbineni, H., Al-Azayzih, A., Peng, X., Hay, N., . . . Somanath, P. R. (2016). Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover. Cellular and Molecular Life Sciences,73(20), 3917-3933.


            The vascular endothelial growth factor (VEGF)¾vascular permeability-inducing¾and Angiopoietin-1 (Ang-1)¾vascular permeability-inhibiting¾both activate Akt1, however, the role of Akt1 in endothelial-barrier regulation is puzzling. The authors analyzed Akt1 knockout mice and Akt1 knockdown human microvascular endothelial cells (HMEC) to determine the long-term role of VEGF/Ang-1 and the importance of Akt1-FOXO signalling in endothelial-barrier protection.

            Recovery following chronic VEGF-induced vascular permeability and endothelial-barrier improvement mediated by chronic Ang-1, is Akt1 dependent, however, acute effects of VEGF and Ang-1 are independent of Akt1. Continual Akt1 activity inhibits vascular permeability and protects the endothelial barrier. FOXO-inhibitors recover endothelial-barrier deficiencies, suggesting the therapeutic potential of targeting FOXO for treatment of vascular permeability-related disorders. 107


Lee, S., Chen, T. T., Barber, C. L., Jordan, M. C., Murdock, J., Desai, S., . . . Iruela-Arispe, M. L. (2007). Autocrine VEGF Signaling Is Required for Vascular Homeostasis. Cell,130(4), 691-703.


            The vascular endothelial growth factor (VEGF) is a signal protein which acts through two receptor tyrosine kinases¾VEGFR1 (role unclear) and VEGFR2 (facilitates angiogenic functions)¾to stimulate the formation of blood vessels. The authors analyzed the role of autocrine VEGF by recording VEGFR2 phosphorylation (activation) in the presence of wild-type or null-VEGF endothelial cells, in the absence of exogenous VEGF. VEGFR2 was phosphorylated in wild-type but not null-VEGF endothelial cells.

            Endothelial degeneration and sudden death occurred in 55% of mutant mice with a deletion of vegf. The results suggest that autocrine VEGF signalling is important for endothelial cell survival. Although VEGFR2 facilitates the activation of both paracrine and autocrine VEGF, paracrine signalling focuses on proliferation and endothelial differentiation, while autocrine signalling is purely for survival signals.

            These findings support an important new model in which sustainability of the endothelium is maintained by the survival signals originating from autocrine VEGF signalling. 148






Gerber, H., Hillan, K. J., Ryan, A. M., Kowalski, J., Keller, G., Rangell, L., . . . Ferrara, N. (1999). VEGF is required for growth and survival in neonatal mice. Development,126(6), 1149-1159.


The vascular endothelial growth factor (VEGF) is essential for embryonic development, however, little is known about its part in postnatal development. The authors used two methods to inactivate VEGF protein in neonatal mice, then analyzed the resulting effects on growth and survival. While partial VEGF inactivation resulted in stunted growth, complete inhibition led to abnormalities in organs and eventually lethal metabolic failure. Endothelial cell apoptosis was greater in the organs of the VEGF knockout mice than was in the organs of the control mice.

Eleven-day-old mice treated with VEGF inhibitors showed increased endothelial apoptosis and mortality, however, 27-day-old mice treated with the same inhibitors only showed inhibited angiogenesis. Therefore, the dependence of newborns on VEGF must change with maturation.

Although the nature of this switch remains a mystery, availability of more advanced knock out technology in mice may be critical in better determining the role of VEGF throughout development and survival, especially in the adult stages. 156