Intrinsic regulation of microvascular tone by myoendothelial feedback circuits

Lemmey, Hamish A.L.; Garland, Christopher; Dora, K A

doi:10.1016/bs.ctm.2020.01.004

Cited by 15 publications

(23 citation statements)

References 65 publications

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“…Endothelial ion channels and cell-cell communication also are involved in myoendothelial feedback. In arterioles and resistance arteries, increases in smooth muscle tone induced by vasoconstrictors result in an increase in endothelial cell [Ca 2+ ] in , activation of IK Ca and SK Ca channels to hyperpolarize the endothelial cells, and activation of production of NO and likely other endothelial cell Ca 2+ -dependent vasodilator autacoids [see Lemmey et al (2020) for a detailed review of this topic]. The hyperpolarization is transmitted back to the smooth muscle through MEGJs, deactivating smooth muscle voltage-gated Ca 2+ channels, and blunting the vasoconstrictor-induced smooth muscle tone.…”

Section: Arteriolar Endothelial Cell Ion Channels and Cell-cell Commu...mentioning

confidence: 99%

Endothelial Ion Channels and Cell-Cell Communication in the Microcirculation

Jackson

2022

Front. Physiol.

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Endothelial cells in resistance arteries, arterioles, and capillaries express a diverse array of ion channels that contribute to Cell-Cell communication in the microcirculation. Endothelial cells are tightly electrically coupled to their neighboring endothelial cells by gap junctions allowing ion channel-induced changes in membrane potential to be conducted for considerable distances along the endothelial cell tube that lines arterioles and forms capillaries. In addition, endothelial cells may be electrically coupled to overlying smooth muscle cells in arterioles and to pericytes in capillaries via heterocellular gap junctions allowing electrical signals generated by endothelial cell ion channels to be transmitted to overlying mural cells to affect smooth muscle or pericyte contractile activity. Arteriolar endothelial cells express inositol 1,4,5 trisphosphate receptors (IP3Rs) and transient receptor vanilloid family member 4 (TRPV4) channels that contribute to agonist-induced endothelial Ca2+ signals. These Ca2+ signals then activate intermediate and small conductance Ca2+-activated K+ (IKCa and SKCa) channels causing vasodilator-induced endothelial hyperpolarization. This hyperpolarization can be conducted along the endothelium via homocellular gap junctions and transmitted to overlying smooth muscle cells through heterocellular gap junctions to control the activity of voltage-gated Ca2+ channels and smooth muscle or pericyte contraction. The IKCa- and SKCa-induced hyperpolarization may be amplified by activation of inward rectifier K+ (KIR) channels. Endothelial cell IP3R- and TRPV4-mediated Ca2+ signals also control the production of endothelial cell vasodilator autacoids, such as NO, PGI2, and epoxides of arachidonic acid contributing to control of overlying vascular smooth muscle contractile activity. Cerebral capillary endothelial cells lack IKCa and SKCa but express KIR channels, IP3R, TRPV4, and other Ca2+ permeable channels allowing capillary-to-arteriole signaling via hyperpolarization and Ca2+. This allows parenchymal cell signals to be detected in capillaries and signaled to upstream arterioles to control blood flow to capillaries by active parenchymal cells. Thus, endothelial cell ion channels importantly participate in several forms of Cell-Cell communication in the microcirculation that contribute to microcirculatory function and homeostasis.

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Section: Arteriolar Endothelial Cell Ion Channels and Cell-cell Commu...mentioning

confidence: 99%

Endothelial Ion Channels and Cell-Cell Communication in the Microcirculation

Jackson

2022

Front. Physiol.

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“…Myoendothelial feedback is critical in regulating the degree of constriction elicited through α-adrenergic activation on VSMCs. This feedback occurs when the inositol 1,4,5-trisphosphate (IP 3 ) generated in VSMC diffuses through myoendothelial gap junctions, where it then activates vasodilatory signaling in ECs as negative feedback regulation [132, 172-176]. Myoendothelial feedback can also occur when calcium from smooth muscle cells transverses the gap junctions to induce vasodilatory signaling in endothelial cells [132, 177].…”

Section: Abluminal Membranementioning

confidence: 99%

Polarized Proteins in Endothelium and Their Contribution to Function

et al. 2021

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Protein localization in endothelial cells is tightly regulated to create distinct signaling domains within their tight spatial restrictions including luminal membranes, abluminal membranes, and interendothelial junctions, as well as caveolae and calcium signaling domains. Protein localization in endothelial cells is also determined in part by the vascular bed, with differences between arteries and veins and between large and small arteries. Specific protein polarity and localization is essential for endothelial cells in responding to various extracellular stimuli. In this review, we examine protein localization in the endothelium of resistance arteries, with occasional references to other vessels for contrast, and how that polarization contributes to endothelial function and ultimately whole organism physiology. We highlight the protein localization on the luminal surface, discussing important physiological receptors and the glycocalyx. The protein polarization to the abluminal membrane is especially unique in small resistance arteries with the presence of the myoendothelial junction, a signaling microdomain that regulates vasodilation, feedback to smooth muscle cells, and ultimately total peripheral resistance. We also discuss the interendothelial junction, where tight junctions, adherens junctions, and gap junctions all convene and regulate endothelial function. Finally, we address planar cell polarity, or axial polarity, and how this is regulated by mechanosensory signals like blood flow.

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“…In addition, TRPV4 channels play a central role in myoendothelial negative-feedback that tempers vascular tone in the absence of an endothelial agonist. Agonist-induced activation of VSMC Gq-coupled receptors leads to a global increase in EC intracellular Ca 2+ ( Dora et al, 1997 ; Schuster et al, 2001 ; Tuttle and Falcone, 2001 ; Jackson et al, 2008 ; Kansui et al, 2008 ) that contributes to the negative-feedback regulation of vascular tone ( Lemmey et al, 2020 ). Studies in murine mesenteric resistance arteries have shown that endothelial TRPV4 channels are activated during this process through a mechanism involving Ca 2+ release through IP 3 Rs, resulting in activation of IK Ca channels blunting agonist-induced vasoconstriction ( Hong et al, 2018 ; Figure 3 ).…”

Section: Endothelial Ca 2+ -Dependent Ion Channels and Arteriolar Tonementioning

confidence: 99%

“…Myoendothelial gap junctions allow this hyperpolarization to be passed from ECs to VSMCs, producing VSMC hyperpolarization, deactivation of VSMC VGCCs and reduced myogenic tone ( Figure 3 ). Thus, the production of EC autacoids and EC membrane potential are both strongly dependent on the activity of Ca 2+ -dependent ion channels in the endothelium including IP 3 Rs, TRPV4 channels, sK Ca channels and IK Ca channels ( Lemmey et al, 2020 ).…”

Section: Integration Of Ca 2+ -Dependent Ion Channels Into the Mechanisms Underlying Pressure-induced Myogenic Tonementioning

confidence: 99%

“…The arteriolar endothelium provides negative-feedback signals to overlying VSMCs through Ca 2+ -dependent autacoid production and direct electrical communication via myoendothelial gap junctions (MEGJs; Lemmey et al, 2020 ). Endothelial Ca 2+ -dependent ion channels contribute to these processes ( Figure 1 ) as outlined in Section Endothelial Ca 2+ -Dependent Ion Channels and Arteriolar Tone, below.…”

Section: Introductionmentioning

confidence: 99%

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Calcium-Dependent Ion Channels and the Regulation of Arteriolar Myogenic Tone

Jackson

2021

Front. Physiol.

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Arterioles in the peripheral microcirculation regulate blood flow to and within tissues and organs, control capillary blood pressure and microvascular fluid exchange, govern peripheral vascular resistance, and contribute to the regulation of blood pressure. These important microvessels display pressure-dependent myogenic tone, the steady state level of contractile activity of vascular smooth muscle cells (VSMCs) that sets resting arteriolar internal diameter such that arterioles can both dilate and constrict to meet the blood flow and pressure needs of the tissues and organs that they perfuse. This perspective will focus on the Ca2+-dependent ion channels in the plasma and endoplasmic reticulum membranes of arteriolar VSMCs and endothelial cells (ECs) that regulate arteriolar tone. In VSMCs, Ca2+-dependent negative feedback regulation of myogenic tone is mediated by Ca2+-activated K+ (BKCa) channels and also Ca2+-dependent inactivation of voltage-gated Ca2+ channels (VGCC). Transient receptor potential subfamily M, member 4 channels (TRPM4); Ca2+-activated Cl− channels (CaCCs; TMEM16A/ANO1), Ca2+-dependent inhibition of voltage-gated K+ (KV) and ATP-sensitive K+ (KATP) channels; and Ca2+-induced-Ca2+ release through inositol 1,4,5-trisphosphate receptors (IP3Rs) participate in Ca2+-dependent positive-feedback regulation of myogenic tone. Calcium release from VSMC ryanodine receptors (RyRs) provide negative-feedback through Ca2+-spark-mediated control of BKCa channel activity, or positive-feedback regulation in cooperation with IP3Rs or CaCCs. In some arterioles, VSMC RyRs are silent. In ECs, transient receptor potential vanilloid subfamily, member 4 (TRPV4) channels produce Ca2+ sparklets that activate IP3Rs and intermediate and small conductance Ca2+ activated K+ (IKCa and sKCa) channels causing membrane hyperpolarization that is conducted to overlying VSMCs producing endothelium-dependent hyperpolarization and vasodilation. Endothelial IP3Rs produce Ca2+ pulsars, Ca2+ wavelets, Ca2+ waves and increased global Ca2+ levels activating EC sKCa and IKCa channels and causing Ca2+-dependent production of endothelial vasodilator autacoids such as NO, prostaglandin I2 and epoxides of arachidonic acid that mediate negative-feedback regulation of myogenic tone. Thus, Ca2+-dependent ion channels importantly contribute to many aspects of the regulation of myogenic tone in arterioles in the microcirculation.

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Intrinsic regulation of microvascular tone by myoendothelial feedback circuits

Cited by 15 publications

References 65 publications

Endothelial Ion Channels and Cell-Cell Communication in the Microcirculation

Endothelial Ion Channels and Cell-Cell Communication in the Microcirculation

Polarized Proteins in Endothelium and Their Contribution to Function

Calcium-Dependent Ion Channels and the Regulation of Arteriolar Myogenic Tone

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