Akt1-dependent expression of angiopoietin 1 and 2 in vascular smooth muscle cells leads to vascular stabilization

Retinal angiogenesis was delayed in VSMC-specific Akt1-deficient mice (Akt1 ∆SMC ) but not in Akt2 ∆SMC mice. The proliferation of ECs, recruitment of pericytes, and coverage of VSMCs to the endothelium were defective in Akt1 ∆SMC . The silencing of Akt1 in VSMCs led to the downregulation of angiopoietin 1 (Ang1) and the upregulation of Ang2. The activation of Notch3 in VSMCs was significantly reduced in the retinas of Akt1 ∆SMC mice. Silencing Akt1 suppressed the activation of Notch3. Moreover, the silencing of Notch3 downregulated Ang1, whereas the overexpression of Notch3 intracellular domain (NICD3) enhanced Ang1 expression. The nuclear localization and transcriptional activity of yes-associated protein (YAP) were affected by the expression level of Akt1. Silencing YAP downregulated Ang2 expression, whereas overexpression of YAP showed the opposite results. Ang1 antibody and Ang2 suppressed endothelial sprouting of wild-type aortic tissues, whereas the Ang2 antibody and Ang1 facilitated the endothelial sprouting of aortic tissues from Akt1 ∆SMC mice. Finally, severe hemorrhage was observed in Akt1 ∆SMC mice, which was further facilitated under streptozotocin (STZ)-induced diabetic conditions. Therefore, the Akt1-Notch3/YAP-Ang1/2 signaling cascade in VSMCs might play an essential role in the paracrine regulation of endothelial function. Blood vessel formation: Nearly identical proteins but different effects Proteins Akt1 and Akt2 are nearly identical, but they play different roles in angiogenesis, the formation of new blood vessels. Angiogenesis is crucial in wound healing and development, and also in tumor formation. Although Akt1’s role in angiogenesis is well studied, the role of other Akt isoforms—highly similar, related proteins—was unknown. Sun Sik Bae at Pusan National University School of Medicine, Yangsan, South Korea, and coworkers investigated how Akt1 and Akt2 influence angiogenesis in the retinas of mice. They found that despite having very similar sequences, Akt2 had almost no effect but Akt1 was crucial for vascular stability. Akt1 boosted levels of the blood vessel stabilization protein Ang1 and suppressed Ang2. Mice lacking Akt1 eventually showed blood vessel leakage. These results illuminate the mechanisms underlying blood vessel formation.