Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Abstract

An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca2+ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca2+ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca2+ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca2+ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca2+ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated Ca2+ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca2+ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca2+]i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca2+ signaling under multiple pathological conditions.

GCN5 contributes to intracellular lipid accumulation in human primary cardiac stromal cells from patients affected by Arrhythmogenic cardiomyopathy

“… 8 The key role of oxidative stress in ACM pathophysiology is confirmed in the present study by the fact that ACM patient biopsies demonstrate higher amount of oxidative stress measured by 4HNE staining compared to CTR donors. Of note, it has been recently demonstrated that lipid peroxidation metabolites, as 4HNE, may activate a robust intracellular Ca 2 + influx through transient receptor potential A1 (TRPA1) channels in the endothelium of cerebral arteries, 53 , 54 thus suggesting that oxidative stress acting on Ca 2+ signalling trough TRP channels might represent an intriguing mechanism involved in the dysfunction of ACM tissues and differentiation of CStCs.…”

“…opsies demonstrate higher amount of oxidative stress measured by 4HNE staining compared to CTR donors. Of note, it has been recently demonstrated that lipid peroxidation metabolites, as 4HNE, may activate a robust intracellular Ca 2+ influx through transient receptor potential A1 (TRPA1) channels in the endothelium of cerebral arteries,53,54 thus suggesting that oxidative stress acting on Ca 2+ signalling trough TRP channels might represent an intriguing mechanism involved in the dysfunction of ACM tissues and differentiation of CStCs.Further, MB-3 treatment of ACM CStCs seemed to protect from mitochondrial ROS production, as demonstrated by decreased MitoSOX fluorescence intensity, thus highlighting a possible specific functional role for mitochondria in the disease 55. Notably, MB-3 also boosted cellular detoxification systems by acting on glutathione homeostasis slightly increasing reduced glutathione (GSH) and significantly increasing oxidized glutathione (GSSG) levels.…”

Oxidative stress in melanogenesis and melanoma development

“…Although ROS are generated mostly in mitochondria and endoplasmic reticulum, they can be produced in other intracellular structures such as peroxisomes and melanosomes [ 1 , 3 ]. Melanosomes constitute the lysosome-related organelles in melanocytes where melanin synthesis takes place.…”

Oxidative Stress Induced by High Salt Diet—Possible Implications for Development and Clinical Manifestation of Cutaneous Inflammation and Endothelial Dysfunction in Psoriasis vulgaris

“…•− to G protein/receptor-mediated signaling in endothelial cells in the aortas of rats fed a HS diet [66]. Given that multiple recent studies have shown that ROS induces an increase of [Ca 2+ ] i in endothelial cells, an effect attenuated by the addition of ROS scavengers, the mechanisms of HS dietary load on this attenuated amplitude of the [Ca 2+ ] i increase in the rat aorta have yet to be elucidated [77,78].…”

“…Zhu et al suggested that the possible explanation for this difference in acute and chronic Tempol exposure on the Ca 2+ signaling pathways in HS diet might be due to the damage caused by the continuously elevated O 2 ●− to G protein/receptor-mediated signaling in endothelial cells in the aortas of rats fed a HS diet [ 66 ]. Given that multiple recent studies have shown that ROS induces an increase of [Ca 2+ ] i in endothelial cells, an effect attenuated by the addition of ROS scavengers, the mechanisms of HS dietary load on this attenuated amplitude of the [Ca 2+ ] i increase in the rat aorta have yet to be elucidated [ 77 , 78 ].…”