Canagliflozin Inhibits Human Endothelial Cell Proliferation and Tube Formation

Abstract

Recent clinical trials revealed that sodium-glucose co-transporter 2 (SGLT2) inhibitors significantly reduce cardiovascular events in type 2 diabetic patients, however, canagliflozin increased limb amputations, an effect not seen with other SGLT2 inhibitors. Since endothelial cell (EC) dysfunction promotes diabetes-associated vascular disease and limb ischemia, we hypothesized that canagliflozin, but not other SGLT2 inhibitors, impairs EC proliferation, migration, and angiogenesis. Treatment of human umbilical vein ECs (HUVECs) with clinically relevant concentrations of canagliflozin, but not empagliflozin or dapagliflozin, inhibited cell proliferation. In particular, 10 μM canagliflozin reduced EC proliferation by approximately 45%. The inhibition of EC growth by canagliflozin occurred in the absence of cell death and was associated with diminished DNA synthesis, cell cycle arrest, and a striking decrease in cyclin A expression. Restoration of cyclin A expression via adenoviral-mediated gene transfer partially rescued the proliferative response of HUVECs treated with canagliflozin. A high concentration of canagliflozin (50 μM) modestly inhibited HUVEC migration by 20%, but markedly attenuated their tube formation by 65% and EC sprouting from mouse aortas by 80%. A moderate 20% reduction in HUVEC migration was also observed with a high concentration of empagliflozin (50 μM), while neither empagliflozin nor dapagliflozin affected tube formation by HUVECs. The present study identified canagliflozin as a robust inhibitor of human EC proliferation and tube formation. The anti-proliferative action of canagliflozin occurs in the absence of cell death and is due, in part, to the blockade of cyclin A expression. Notably, these actions are not seen with empagliflozin or dapagliflozin. The ability of canagliflozin to exert these pleiotropic effects on ECs may contribute to the clinical actions of this drug.

Dapagliflozin Promotes Neovascularization by Improving Paracrine Function of Skeletal Muscle Cells in Diabetic Hindlimb Ischemia Mice Through PHD2/HIF-1α Axis

“…Meanwhile, the angiogenic factors secreted by dapagliflozin-treated skeletal muscle cells could stimulate both vascular endothelial and smooth muscle cells’ proliferation and migration potentials. These results are consistent with those of previous studies, showing that 10 μM dapagliflozin did not affect the proliferation and migration of vascular endothelial cells ( Mancini et al., 2018 ; Behnammanesh et al., 2019 ), as well as those of smooth muscle cells ( Behnammanesh et al., 2020 ). Together, these results suggest that intramuscularly-administered dapagliflozin exerts its function in inducing neovascularization and blood perfusion recovery by promoting the paracrine function of skeletal muscle cells, which in turn enhances the proliferation and migration potentials of vascular endothelial and smooth muscle cells.…”

Crosstalk between H1975 tumor cells and platelets to induce the proliferation, migration and tube formation of vascular endothelial cells

“…It was speculated that tumor-PLT crosstalk can enhance the tube formation ability of HUVECs. Tube-forming experiments are a rapid and quantifiable method to measure angiogenesis in vitro ( 41 ). The present study investigated the effect of H1975-PLT crosstalk on HUVEC angiogenesis using junction number, mesh number and total length as indicators of tube-forming ability, and the results of the present study confirmed that the tube-forming ability of HUVECs could be promoted by H1975-PLT crosstalk.…”

Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer’s Disease and Ischemia-Related Brain Injury

“…Another SGLT2 inhibitor, canagliflozin has proven to be an inhibitor of endothelial cells (ECs) proliferation and DNA synthesis [ 84 ]. The process of controlling EC growth has been shown to play a pivotal role in atherogenesis inhibition [ 85 ].…”