Cracking the Endothelial Calcium (Ca2+) Code: A Matter of Timing and Spacing

Abstract

A monolayer of endothelial cells lines the innermost surface of all blood vessels, thereby coming into close contact with every region of the body and perceiving signals deriving from both the bloodstream and parenchymal tissues. An increase in intracellular Ca2+ concentration ([Ca2+]i) is the main mechanism whereby vascular endothelial cells integrate the information conveyed by local and circulating cues. Herein, we describe the dynamics and spatial distribution of endothelial Ca2+ signals to understand how an array of spatially restricted (at both the subcellular and cellular levels) Ca2+ signals is exploited by the vascular intima to fulfill this complex task. We then illustrate how local endothelial Ca2+ signals affect the most appropriate vascular function and are integrated to transmit this information to more distant sites to maintain cardiovascular homeostasis. Vasorelaxation and sprouting angiogenesis were selected as an example of functions that are finely tuned by the variable spatio-temporal profile endothelial Ca2+ signals. We further highlighted how distinct Ca2+ signatures regulate the different phases of vasculogenesis, i.e., proliferation and migration, in circulating endothelial precursors.

Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age

“…Additionally, in rat hippocampal neurons, AMPARs trigger the association of the G i/o proteinderived β subunit with voltage-gated Na + channels, thereby inducing Na + entry that promotes mitochondrial Ca 2+ release by reversing the mitochondrial Na + /Ca 2+ exchanger (Figure 1) [33]. Furthermore, flux-independent signaling by AMPARs stimulates the migration of rat oligodendrocyte progenitor cells by inducing the formation of a α V /myelin proteolipid protein complex, which in turn elicits a pro-migratory oscillatory Ca 2+ signal [34,35]. Recruitment of G i/o proteins is also used by AMPARs to inhibit the expression of the Arc gene (Figure 1) [36], which is critical for maintaining synaptic potentiation and long-term consolidation of memory [37].…”

“…Endothelial cells line the inner lumen of blood vessels and are therefore critical for regulating the exchange of solutes between the streaming blood and parenchymal tissues [35,219]. The primary role of CECs has long been associated with the maintenance of the structural and functional integrity of the BBB [220].…”

Increased TRPV4 channel expression enhances and impairs blood vessel function in hypertension

“…The release of endothelium-derived relaxing and contracting factors is triggered by changes in cytosolic Ca 2+ concentration [11][12][13][14] . The regulation of endothelial Ca 2+ involves both internal and extracellular sources 15 . Primarily, Ca 2+ release from the internal store is mediated by IP 3 receptors 16 and several Ca 2+ channels expressed on the plasmalemma membrane control Ca 2+ influx.…”