Functional Interaction among K _Ca and TRP Channels for Cardiovascular Physiology: Modern Perspectives on Aging and Chronic Disease

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 ([Ca ²⁺] _i) and regulation of membrane potential (V _m) is indispensable for maintaining blood flow regulation. In particular, Ca ²⁺-activated K ⁺ (K _Ca) channels were ascertained as transducers of elevated [Ca ²⁺] _i signals into hyperpolarization of V _m as a pathway for decreasing vascular resistance, thereby enhancing blood flow. Recent evidence also supports the reverse role for K _Ca channels, in which they facilitate Ca ²⁺ 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 Ca ²⁺. Such an arrangement supports a feed-forward activation of V _m hyperpolarization while potentially boosting production of nitric oxide. Furthermore, in vascular types expressing TRP channels but deficient in functional K _Ca 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 K _Ca and TRP channels throughout multiple experimental animal models and vascular types. We discuss the diverse interactions among K _Ca and TRP channels to integrate Ca ²⁺, 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.