Abstract
Effective delivery of oxygen and essential nutrients to vital organs and tissues throughout the body requires adequate blood flow supplied through resistance vessels. The intimate relationship between intracellular calcium ([Ca2+]i) and regulation of membrane potential (Vm) is indispensable for maintaining blood flow regulation. In particular, Ca2+-activated K+ (KCa) channels were ascertained as transducers of elevated [Ca2+]i signals into hyperpolarization of Vm as a pathway for decreasing vascular resistance, thereby enhancing blood flow. Recent evidence also supports the reverse role for KCa channels, in which they facilitate Ca2+ influx into the cell interior through open non-selective cation (e.g., transient receptor potential; TRP) channels in accord with robust electrical (hyperpolarization) and concentration (~20,000-fold) transmembrane gradients for Ca2+. Such an arrangement supports a feed-forward activation of Vm hyperpolarization while potentially boosting production of nitric oxide. Furthermore, in vascular types expressing TRP channels but deficient in functional KCa channels (e.g., collecting lymphatic endothelium), there are profound alterations such as downstream depolarizing ionic fluxes and the absence of dynamic hyperpolarizing events. Altogether, this review is a refined set of evidence-based perspectives focused on the role of the endothelial KCa and TRP channels throughout multiple experimental animal models and vascular types. We discuss the diverse interactions among KCa and TRP channels to integrate Ca2+, oxidative, and electrical signaling in the context of cardiovascular physiology and pathology. Building from a foundation of cellular biophysical data throughout a wide and diverse compilation of significant discoveries, a translational narrative is provided for readers toward the treatment and prevention of chronic, age-related cardiovascular disease.
Highlights
Endothelial cells lining the lumen of resistance arteries command changes in vascular diameter as needed to meet the metabolic demand of vital organs and tissues throughout the body
Physiological stimulation of endothelium-derived hyperpolarization (EDH) entails stimulation of Gq-protein-coupled receptors (GqPCRs) and an increase in [Ca2+]i typically defined by initial Ca2+ release from the endoplasmic reticulum (ER) followed by a “plateau” phase
There are limits to the effectiveness of SKCa/IKCa channel activation, vasodilation, and the delivery of blood flow, as we found that hyperpolarization of Vm >−60 mV results in current leak that reduces the spread of hyperpolarization among endothelial cells by more than half [37,38]
Summary
Endothelial cells lining the lumen of resistance arteries command changes in vascular diameter as needed to meet the metabolic demand of vital organs and tissues throughout the body. With the use of an endothelium-specific SK3 knock-out mouse model, it was found that the coupling of SK3 and TRPV4 channels in mesenteric arteries appears to elicit large-amplitude and slow-decay Ca2+ kinetics that may be consistent with relatively long-term physiological delivery of blood flow in response to metabolic demand of active tissues [55] Another foundational study demonstrated how small (diameter: ~100 μm) mesenteric endothelial TRPV4 channel-mediated Ca2+ “sparklets” activate SKCa and IKCa channels using wild-type, endothelial genetic Ca2+ sensor (GCaMP2Cx40) and TRPV4−/− mice and customized Ca2+ event detection software; only a few open TRPV4 channels are required for maximal vasodilation [83]. As a clearer foundation for understanding mammalian cardiovascular function and pathology, focus on the impact of aging and associated pathology (primarily using rodent models) is discussed
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