The Role of Endothelial Ca2+ Signaling in Neurovascular Coupling: A View from the Lumen

Abstract

Background: Neurovascular coupling (NVC) is the mechanism whereby an increase in neuronal activity (NA) leads to local elevation in cerebral blood flow (CBF) to match the metabolic requirements of firing neurons. Following synaptic activity, an increase in neuronal and/or astrocyte Ca2+ concentration leads to the synthesis of multiple vasoactive messengers. Curiously, the role of endothelial Ca2+ signaling in NVC has been rather neglected, although endothelial cells are known to control the vascular tone in a Ca2+-dependent manner throughout peripheral vasculature. Methods: We analyzed the literature in search of the most recent updates on the potential role of endothelial Ca2+ signaling in NVC. Results: We found that several neurotransmitters (i.e., glutamate and acetylcholine) and neuromodulators (e.g., ATP) can induce dilation of cerebral vessels by inducing an increase in endothelial Ca2+ concentration. This, in turn, results in nitric oxide or prostaglandin E2 release or activate intermediate and small-conductance Ca2+-activated K+ channels, which are responsible for endothelial-dependent hyperpolarization (EDH). In addition, brain endothelial cells express multiple transient receptor potential (TRP) channels (i.e., TRPC3, TRPV3, TRPV4, TRPA1), which induce vasodilation by activating EDH. Conclusions: It is possible to conclude that endothelial Ca2+ signaling is an emerging pathway in the control of NVC.

Type 2 Diabetes Alters Intracellular Ca2+ Handling in Native Endothelium of Excised Rat Aorta

“…Moreover, sprouting angiogenesis, which drives the formation of new capillaries from pre-existing microvessels, is exacerbated in the retina, thereby resulting in retinopathy [9].An increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) is crucial to fine tune endothelial cell functions [10][11][12]. For instance, endothelial Ca 2+ signals drive the release of many vasodilators, including nitric oxide, prostacyclin, arachidonic acid metabolites and hydrogen sulfide, and recruit Ca 2+ -activated K + channels to stimulate endothelium-dependent hyperpolarization [13][14][15][16]. In addition, an increase in endothelial [Ca 2+ ] i leads to the production of the vasoconstrictor prostanoids, thromboxane A2, prostaglandin H2 and endothelin-1 [14,17,18].…”

“…For instance, endothelial Ca 2+ signals drive the release of many vasodilators, including nitric oxide, prostacyclin, arachidonic acid metabolites and hydrogen sulfide, and recruit Ca 2+ -activated K + channels to stimulate endothelium-dependent hyperpolarization [13][14][15][16]. In addition, an increase in endothelial [Ca 2+ ] i leads to the production of the vasoconstrictor prostanoids, thromboxane A2, prostaglandin H2 and endothelin-1 [14,17,18]. Vasoactive agonists bind to specific G-protein coupled receptors to engage phospholipase Cβ, a membrane-bound enzyme that cleaves inositol-1,4,5-trisphosphate (InsP 3 ) from its precursor phosphatidylinositol-4,5-bisphosphate [14,15].…”

“…In addition, an increase in endothelial [Ca 2+ ] i leads to the production of the vasoconstrictor prostanoids, thromboxane A2, prostaglandin H2 and endothelin-1 [14,17,18]. Vasoactive agonists bind to specific G-protein coupled receptors to engage phospholipase Cβ, a membrane-bound enzyme that cleaves inositol-1,4,5-trisphosphate (InsP 3 ) from its precursor phosphatidylinositol-4,5-bisphosphate [14,15]. The following Ca 2+ response typically consists of an initial Ca 2+ peak, which is mediated by InsP 3 -induced Ca 2+ release from the endoplasmic reticulum (ER), followed by a prolonged influx of Ca 2+ , known as a plateau [19,20].…”

Endothelial Transient Receptor Potential Channels and Vascular Remodeling: Extracellular Ca2 + Entry for Angiogenesis, Arteriogenesis and Vasculogenesis

“…Likewise, VEGF and SDF-1α induce pro-angiogenic Ca 2+ signals in endothelial colony forming cells (ECFCs) (Dragoni et al, 2011(Dragoni et al, , 2013Zuccolo et al, 2018;Moccia, 2020), which represent the only EPC subtype truly belonging to the vascular endothelial lineage (Medina et al, 2017;Poletto et al, 2018). Transient Receptor Potential (TRP) channels regulate numerous endothelial cell functions by mediating extracellular Ca 2+ entry in response to chemical, mechanical and thermal stimuli (Moccia et al, 2012a;Earley and Brayden, 2015;Guerra et al, 2018;Smani et al, 2018;Thakore and Earley, 2019). Herein, we describe how endothelial TRP channels stimulate vascular remodeling by promoting angiogenesis, arteriogenesis and vasculogenesis through the FIGURE 1 | Vasculogenesis and angiogenesis are the main processes responsible for vascular remodeling.…”

Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish

“…Interactions between these ensures neuronal energy demands are met through increased local blood flow via neurovascular coupling (NVC) (Roy & Sherrington, 1890;Attwell et al, 2010). Recent evidence suggests that ECs are crucial to NVU function (Toth et al, 2015;Guerra et al, 2018) as they release vasoactive substances such as nitric oxide (NO) (Ignarro et al, 1987;Palmer et al, 1987). NO production is regulated by various endothelial genes including the Kruppel-like family of transcription factors (KLFs) (Gracia-Sancho et al, 2011) particularly KLF2 which is regulated by changes in flow and inflammation (Dekker et al, 2002;SenBanerjee et al, 2004b).…”