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Calcium signals that determine vascular resistance

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Small arteries in the body control vascular resistance, and therefore, blood pressure and blood flow. Endothelial and smooth muscle cells in the arterial walls respond to various stimuli by altering the vascular resistance on a moment to moment basis. Smooth muscle cells can directly influence arterial diameter by contracting or relaxing, whereas endothelial cells that line the inner walls of the arteries modulate the contractile state of surrounding smooth muscle cells. Cytosolic calcium is a key driver of endothelial and smooth muscle cell functions. Cytosolic calcium can be increased either by calcium release from intracellular stores through IP3 or ryanodine receptors, or the influx of extracellular calcium through ion channels at the cell membrane. Depending on the cell type, spatial localization, source of a calcium signal, and the calcium‐sensitive target activated, a particular calcium signal can dilate or constrict the arteries. Calcium signals in the vasculature can be classified into several types based on their source, kinetics, and spatial and temporal properties. The calcium signaling mechanisms in smooth muscle and endothelial cells have been extensively studied in the native or freshly isolated cells, therefore, this review is limited to the discussions of studies in native or freshly isolated cells. This article is categorized under: Biological Mechanisms > Cell Signaling Laboratory Methods and Technologies > Imaging Models of Systems Properties and Processes > Mechanistic Models
Ca2+ signaling networks in VSMCs. (a) Voltage‐dependent Ca2+ channel (VDCC)‐mediated signaling mechanisms that regulate vascular smooth muscle cell (VSMC) contractility. Ca2+ influx through CaV1.2, CaV3.1, and CaV3.3 channels, and Ca2+ release through IP3Rs contribute to vasoconstriction. Gq protein coupled receptor (GqPCR) signaling increases Ca2+ levels via activation of IP3 receptors (IP3Rs) and CaV1.2 channels. Ca2+ influx through CaV3.2 channels couples with ryanodine receptors (RyRs) and Ca2+‐activated K+ (BK) channels to cause membrane hyperpolarization and vasodilation. (b) Non‐VDCC Ca2+ influx pathways in VSMCs include transient receptor potential canonical (TRPC) and transient receptor potential vanilloid (TRPV) channels. Ca2+ influx through VSMC TRP channel has mostly been associated with vasoconstriction. Localized Ca2+ influx through TRPV4 channels can activate RyR‐BK channel signaling and contribute to vasodilation. Increase in cytosolic Ca2+ mediated by VDCCs and TRP channels is amplified by Ca2+ release through IP3 receptors (IP3Rs). ER: endoplasmic reticulum; SERCA: sarco/endoplasmic reticulum Ca2+‐ATPase; CaM: Calmodulin; IP3: Inositol triphospate; GqPCR: Gq protein‐coupled receptor; RyR: ryanodine receptor; MLCK: myosin light‐chain kinase; PLC: phospholipase C; PKC: protein kinase C; DAG: diacylglycerol; AT1R: angiotensin II receptor 1; P2X1R: purinergic receptor P2X1
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Ca2+ signaling networks in ECs. (a) Ca2+ influx through TRPV4, TRPA1, and TRPV3 channels, and IP3R‐mediated Ca2+ release from the ER at myoendothelial projections (MEPs) activate IK (intermediate conductance Ca2+‐activated potassium) and SK (small conductance Ca2+‐activated potassium) channels. IK/SK channel activation results in membrane hyperpolarization that is transmitted to vascular smooth muscle cells (VSMCs) via myoendothelial gap junctions (MEGJs). VSMC hyperpolarization then deactivates VDCCs, resulting in vasodilation. (b) IP3R‐mediated Ca2+ release from the ER and Ca2+ influx through TRPV4 channels at the MEPs have been associated with myoendothelial feedback mechanism that limits VSMC contraction. Activation of VSMC GqPCR signaling results in the flux of IP3 and/or Ca2+ from VSMCs to ECs via MEGJs. IP3/Ca2+ can activate IP3Rs and TRPV4 channels at the MEPs, resulting in IK/SK channel‐dependent vasodilation. (c) Increase in endothelial Ca2+ can also activate the release of nitric oxide or hyperpolarizing factors that can act on VSMCs. Additionally, intercellular propagation of Ca2+ waves involves the transfer of IP3 and/or Ca2+ between the neighboring ECs (endothelial cell) and Ca2+‐induced Ca2+ release. MEP: myoendothelial projection; ER: endoplasmic reticulum; GqPCR: G‐protein coupled receptor; PKC: protein kinase C; DAG: diacylglycerol; VDCC: voltage dependent Ca2+ channel; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; EDHF: endothelial derived hyperpolarization factor
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Laboratory Methods and Technologies > Imaging
Models of Systems Properties and Processes > Mechanistic Models
Biological Mechanisms > Cell Signaling

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