The Activation of Endothelial Cells Relies on a Ferroptosis-Like Mechanism: Novel Perspectives in Management of Angiogenesis and Cancer Therapy

Abstract

The activation of endothelial cells (ECs) is a crucial step on the road map of tumor angiogenesis and expanding evidence indicates that a pro-oxidant tumor microenvironment, conditioned by cancer metabolic rewiring, is a relevant controller of this process. Herein, we investigated the contribution of oxidative stress-induced ferroptosis to ECs activation. Moreover, we also addressed the anti-angiogenic effect of Propranolol. We observed that a ferroptosis-like mechanism, induced by xCT inhibition with Erastin, at a non-lethal level, promoted features of ECs activation, such as proliferation, migration and vessel-like structures formation, concomitantly with the depletion of reduced glutathione (GSH) and increased levels of oxidative stress and lipid peroxides. Additionally, this ferroptosis-like mechanism promoted vascular endothelial cadherin (VE-cadherin) junctional gaps and potentiated cancer cell adhesion to ECs and transendothelial migration. Propranolol was able to revert Erastin-dependent activation of ECs and increased levels of hydrogen sulfide (H2S) underlie the mechanism of action of Propranolol. Furthermore, we tested a dual-effect therapy by promoting ECs stability with Propranolol and boosting oxidative stress to induce cancer cell death with a nanoformulation comprising selenium-containing chrysin (SeChry) encapsulated in a fourth generation polyurea dendrimer (SeChry@PUREG4). Our data showed that novel developments in cancer treatment may rely on multi-targeting strategies focusing on nanoformulations for a safer induction of cancer cell death, taking advantage of tumor vasculature stabilization.

Aryl Hydrocarbon Receptor and Cysteine Redox Dynamics Underlie (Mal)adaptive Mechanisms to Chronic Intermittent Hypoxia in Kidney Cortex

“…Recently, Lopes-Coelho (2021) showed that the angiogenic process may rely on a ferroptosis-like mechanism in endothelial cells, promoted by the blockage of xCT-related cystine cellular uptake [ 39 ]. Cystine avoids ferroptosis and increases glutathione availability, which avoids the angiogenic switch and promotes vessel stabilization.…”

“…Human umbilical vein endothelial cells (HUVECs: ATCC ® CRL-1730™) were obtained from American Type Culture Collection (ATCC) and cultured in Endothelial Cell Growth Basal Medium-2 (EBM-2: CC-3156, Lonza Bioscience, Basel, Switzerland) supplemented with EGM-2 SingleQuots Supplements (CC-4176, Lonza Bioscience), at 37 °C in a humidified environment of 5% CO 2 , according to previous experience [ 39 ]. HUVECs (2 × 10 5 cells/well) were plated in 6-well plates and exposed to cysteine (0.2, 0.4 and 0.8 mM) and cystine (0.1, 0.2 and 0.4 mM) for 6 and 24 h [ 40 , 41 , 42 ].…”

PIEZO1 Ion Channel Mediates Ionizing Radiation-Induced Pulmonary Endothelial Cell Ferroptosis via Ca2+/Calpain/VE-Cadherin Signaling

“…Calpain inhibitor (PD151746) blocked these effects. VE-cadherin participates in ferroptosis-like mechanism by increasing endothelial cell junction gaps ( Lopes-Coelho et al, 2021 ). Furthermore, E-cadherin, analog of VE-cadherin, has been shown to regulate ferroptosis through activating intracellular NF2-YAP signaling pathway ( Wu et al, 2019b ).…”

“…Increased degradation of VE-cadherin has also been found to cause cerebrovascular dysfunction ( Bhatia et al 2021 ), ventilation-induced lung vascular hyperpermeability ( Jiang L. et al 2021 ) and lung edema ( Cowan et al, 2010 ). Previous studies have recently established that increase in VE-cadherin internalization occurred in erastin-induced endothelial cell ferroptosis ( Stockwell et al, 2017 ; Lopes-Coelho et al, 2021 ). E-cadherin, analog of VE-cadherin, regulates ferroptosis ( Wu et al, 2019a ).…”

Cancer-Induced Metabolic Rewiring of Tumor Endothelial Cells

“…In addition, EC treatment with erastin, an inhibitor of xCT, at a non-lethal level promotes EC proliferation, migration, and vessel-like structures formation, concomitantly with a reduction of GSH and an increase in ROS. The dual therapy using propranolol, which reverts the erastin-dependent activation of ECs, and chrysin to induce cytotoxic to cancer cells, has been proposed [ 100 ].…”