Functional Interaction among K_Ca and TRP Channels for Cardiovascular Physiology: Modern Perspectives on Aging and...

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 (V_m) is indispensable for maintaining blood flow regulation. In particular, Ca²⁺-activated K⁺ (K_Ca) channels were ascertained as transducers of elevated [Ca²⁺]_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 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 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 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.