Inhibition of the PI3K–Akt and mTORC1 signaling pathways promotes the elongation of vascular endothelial cells

Abstract

Endothelial cell morphology needs to be properly regulated during angiogenesis. Vascular endothelial growth factor (VEGF) induces endothelial cell elongation, which promotes sprouting of pre-existing vessels. However, therapeutic angiogenesis using VEGF has been hampered by side effects such as elevated vascular permeability. Here, we attempted to induce endothelial cell elongation without an overdose of VEGF. By screening a library of chemical inhibitors, we identified phosphatidylinositol 3-kinase (PI3K)-Akt pathway inhibitors and mammalian target of rapamycin complex 1 (mTORC1) inhibitors as potent inducers of endothelial cell elongation. The elongation required VEGF at a low concentration, which was insufficient to elicit the same effect by itself. The elongation also depended on Foxo1, a transcription factor indispensable for angiogenesis. Interestingly, the Foxo1 dependency of the elongation was overridden by inhibition of mTORC1, but not by PI3K-Akt, under stimulation by a high concentration of VEGF. Dual inhibition of mTORC1 and mTORC2 failed to induce cell elongation, revealing mTORC2 as a positive regulator of elongation. Our findings suggest that the PI3K-AktFoxo1 and mTORC1-mTORC2 pathways differentially regulate endothelial cell elongation, depending on the microenvironmental levels of VEGF.

PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia

“…PI3K signalling is activated by various growth factors, including VEGF43. Our data show that VEGF signalling is increased in ALK1 mutant cells.…”

Putting VE-cadherin into JAIL for junction remodeling

“…Importantly, VE-cadherin expression remains constant during cell growth (Lampugnani et al, 1995; and after treatment with the proangiogenic growth factor VEGF or the γ-secretase inhibitor DAPT, which also induces angiogenesis (Cao et al, 2017). These treatments all cause a change in cell shape from polygonal to elongated cells (Tsuji-Tamura and Ogawa, 2016;Cao et al, 2017). This results in an increased length of cell junctions, which dilutes the given amount of VE-cadherin along the junctions accordingly.…”

“…Indeed, cell elongation occurs in angiogenesis in vivo in the mouse retina and in zebrafish, and can also be induced in vitro by pro-angiogenic factors, such as VEGF and the γ-secretase inhibitor DAPT (Sauteur et al, 2014; Tsuji-Tamura and Ogawa, 2016; Cao et al, 2017;Paatero et al, 2018). The signals underlying cell elongation involve the loss of tension and microtubule polarization, as well as Rac, PI3K, Foxo1 and mTOR signaling (Furuyama et al, 2004;Tsuji-Tamura and Ogawa, 2016;Cao et al, 2017). The loss of tension accompanies the formation of invaginations, which might increase the cell junction length; this, in turn, decreases Rel-VEcad-C, inducing JAIL formation and thus affects local cell junction dynamics (see above), which is required for the initiation of cell elongation.…”

Critical role for PI3Kγ-dependent neutrophil reactive oxygen species in WKYMVm-induced microvascular hyperpermeability

“…Previous studies revealed that PI3K‐mediated signaling in mast cells can regulate vascular leakage in asthma . The histamine released from mast cells resulted in the disruption of endothelial cell function via PI3K/Akt signaling pathway . PI3K signaling was also involved in sphingosine‐1‐phosphate receptor‐2 (S1PR2)‐mediated paracellular permeability increases by opening adherens junctions between the neighboring endothelial cells .…”