Endothelial Calcium Dysregulation as an Early Trigger of Vascular Dysfunction: Insights into Heavy Metal Toxicity : Heavy Metals and Endothelial Ca2+ Dysregulation.

Endothelial intracellular calcium (Ca2+) signaling is a multi-scale control system that couples external stimuli (shear stress, vasoactive agonists, inflammatory mediators) to nitric oxide (NO) production, endothelium-derived hyperpolarization, barrier integrity, angiogenesis, and regulated exocytosis of prothrombotic mediators. Contemporary "endothelial Ca2+ code" frameworks emphasize that spatially restricted microdomain events, such as TRPV4 "sparklets," IP3R "pulsars/wavelets," and Piezo1-driven mechanochemical transduction, are decoded into functionally specific outputs, while organellar Ca2+ handling from the ER/SR and the mitochondria tunes amplitude, duration, and translation into redox/inflammatory responses. This framework is particularly relevant for toxicology because divalent toxicants can alter not only the magnitude but also the spatial logic of endothelial Ca2+ signaling (Moccia et al. 2023).Heavy metals and metalloids, including lead (Pb), cadmium (Cd), mercury (Hg; particularly methylmercury), and inorganic arsenic (As), are increasingly recognized as cardiovascular risk factors capable of perturbing this endothelial Ca2+ code early in exposure. Mechanistically, these toxicants (i) impersonate Ca2+ or opportunistically bind Ca2+-binding motifs, (ii) enter through or modulate Ca2+-permeable channels (notably TRP and store-operated pathways), (iii) impair pumps/exchangers or provoke ER stress, and (iv) trigger oxidative stress and inflammatory signaling that reciprocally reshapes Ca2+ dynamics and NO bioavailability. The resulting Ca2+/redox feed-forward loops can shift the endothelium toward vasoconstriction, permeability, leukocyte adhesion, dysregulated angiogenesis, and thrombosis. Experimental studies of Pb2+ cardiotoxicity and Ca2+ antagonism, together with broader exposome analyses of Pb and Hg, support the concept that divalent toxicants can act as calcium-mimetic cardiovascular stressors with direct consequences for calcium-dependent signaling (Chavarría et al. 2021; de Mattos et al. 2017; Ferreira et al. 2021a).This review synthesizes endothelial Ca2+ physiology; molecular Ca2+ handling nodes (channels, pumps, exchangers; ER/SR and mitochondria); evidence that Pb, Hg, Cd, and As disrupt Ca2+ homeostasis; downstream dysfunction phenotypes; dose-response and population vulnerability considerations; experimental models and methods; and mitigation strategies and knowledge gaps.