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Ca 2+ signaling events are essential for maintaining cardiovascular health, regulating critical functions in both endothelial and cardiac cells. SARS-CoV-2 infection impinges this delicate balance, leading to severe cardiovascular complications. SARS-CoV-2 binds to the ACE2 receptor on endothelial and cardiomyocyte surfaces, triggering abnormal increases in intracellular Ca 2+ levels that promote endothelial dysfunction, inflammation, and hypercoagulation. In endothelial cells, this dysregulation activates a pro-inflammatory state and compromises vascular integrity. In cardiomyocytes, SARS-CoV-2-induced Ca 2+ imbalances contribute to arrhythmias and heart failure by promoting abnormal Ca 2+ cycling and energy metabolism disruptions. Additionally, the cytokine storm associated with COVID-19 amplifies these effects by further altering Ca 2+ handling, enhancing inflammatory responses, and promoting thrombosis. Targeting Ca 2+ channels, particularly endolysosomal two-pore channels, represents a promising therapeutic approach to counteract SARS-CoV-2's effects on Ca 2+ dynamics. Several FDA-approved drugs that modulate Ca 2+ signaling could be repurposed to prevent viral entry and mitigate cardiovascular damage. Understanding these Ca 2+ -related mechanisms offers valuable insights for developing treatments to reduce cardiovascular risk in COVID-19 and potentially future viral infections impacting the cardiovascular system., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purinergic signaling plays a crucial role in vascular endothelium functions. In particular, ionotropic P2X receptors (P2XRs) are engaged in various intracellular pathways through which endothelial cells (ECs) adapt to external stimuli. However, very little is known about the impact of P2XRs on vascular remodeling during carcinogenesis. We previously demonstrated that high purinergic stimulation impairs the migratory phenotype of tumor-derived endothelial cells (TECs) but not of normal ECs. Since P2XRs are sensitive to different physical and chemical factors, we investigated the impact of tumor microenvironment (TME) on healthy ECs to verify the ability of cancer cells to affect endothelial migratory phenotype through purinergic signaling tuning. More specifically, we focused on P2XR modulation by two different types of TME, mimicking breast and pancreas cancer milieux, which show very different features in terms of vascularization and composition. ECs conditioning with both cancer cell types induced a significant upregulation of some of the most represented P2XR. However, only conditioning with MCF-7 cells and not that with PANC-1 cells was able to alter the migratory phenotype of normal ECs supporting a P2XR-mediated inhibition of cell migration. The differences observed between the two cancer cells could be due to their different proliferative potential and the subsequent different extracellular pH. In addition, in agreement with some of our previous data, the P2XR-induced inhibition of EC migration seems to be independent of calcium signals, as conditioned ECs didn't reveal any changes in the long-lasting responses evoked by purinergic agonists. Collectively, highlighting a significant P2RX modulation by TME, our data strengthen the hypothesis that purinergic signaling may play a central role in vascular remodeling during carcinogenesis. However, the molecular routes upstream and downstream of this modulation remain to be elucidated., (Copyright © 2024.)