Advances and Current Challenges in Calcium Signaling within the Cardiovascular System

The role of calcium signaling in the cardiovascular system goes far beyond its involvement in the "excitation-contraction" coupling in cardiomyocytes and vascular smooth muscle cells. Intracellular Ca²⁺ signals finely tune endothelial functions, thereby regulating also vascular tone and permeability, angiogenesis and vasculogenesis, coagulation and inflammation. An increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) can be achieved through the concerted interaction among the components of a versatile network of membrane receptors, ion channels, transporters and buffers that can be uniquely assembled by each cell type to produce distinct spatio-temporal Ca²⁺ signals that are selectively tailored to adjust specific cardiovascular functions. However, rewiring of the Ca²⁺ handling machinery drives or is intimately involved in many cardiovascular diseases, including cardiac hypertrophy, chronic heart failure, ventricular and atrial arrhythmias, vascular proliferative disorders (atherosclerosis and hypertention), and diabetes.

Furthermore, emerging evidence indicates that the endothelial Ca²⁺ toolkit is altered and contributes to sustain several pathologies associated to aberrant or insufficient vascularization, such as intraocular, neurodegenerative and oncological disorders. We are witnessing a fascinating period of ground-breaking discoveries in cardiovascular Ca²⁺ signaling that were boosted by the advent of novel high-speed, 2D and 3D time-lapse imaging techniques, single-wavelength and genetic Ca²⁺ indicators, and electrophysiological tools, such as microelectrode arrays (MEA). In addition, the pathophysiological role of emerging signaling pathways recently started to be fully appreciated in the cardiovascular system. These include, but are not limited to, the mitochondrial Ca²⁺ uniporter, two-pore channels 1 and 2 and nicotinic acid adenine dinucleotipde phosphate (NAADP), mitochondria associated-endoplasmic reticulum membranes (MAMs), Transient Receptor Potential (TRP) channels, STIM and Orai proteins, Piezo Channels, NLRP3 inflammasome, and so on. Finally, human induced pluripotent stem cells (hiPSCs) recently emerged as a novel cellular tool to investigate cardiovascular disorders in a human model which is significantly closer to the patient than classic animal models.

Time, therefore, has come to gather all the information deriving from this wealth of exciting new technological approaches and to pave the way for cardiovascular research of the future. The elucidation of the mechanisms that underlie the increase in [Ca²⁺]_i, disclosing the Ca²⁺-dependent decoders that translate spatio-temporal Ca²⁺ signals into a precise physiological response among the many possibly arising, and understanding how the Ca²⁺ toolkit is rewired in disease is not only of paramount interest for a deeper comprehension of cardiovascular patho-physiology. It is predicted to reveal a pathway for novel pharmacological intervention and therapeutic development.

In this Research Topic, we encourage our colleagues, both top scientists and emerging researchers, to present their cutting-edge research as well as insightful review articles and commentaries on the following sub-topics related to cardiovascular Ca²⁺ signaling:

1) excitation-contraction coupling in cardiomyocytes and vascular smooth muscle cells;
2) heart failure;
3) cardiac arrhythmia;
4) phenotypic switch in vascular smooth muscle cells and vascular remodeling;
5) endothelial signaling;
6) angiogenesis, endothelial permeability, and inflammation;
7) pathologies associated to aberrant/defective vascularization, e.g. intraocular disorders and vascular dementias.