Intracellular Ca
            <sup>2+</sup>
            Silences L-Type Ca
            <sup>2+</sup>
            Channels in Mesenteric Veins

Thakali, Keshari; Kharade, Sujay V.; Sonkusare, Swapnil K.; Rhee, Sung W.; Stimers, Joseph R.; Rusch, Nancy J.

doi:10.1161/circresaha.109.206763

Cited by 22 publications

(15 citation statements)

References 53 publications

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“…In PASMC, L-and T-type VDCC are the main pathways for voltage-mediated Ca 2ϩ influx involved in excitation-contraction coupling and proliferation (16,26,50). In the present study, we show that L-type (Ca v 1.2) and T-type (Ca v 3.2) channels are specifically upregulated in the PA (but not in the MA) of hypoxic mice, suggesting a role for these channels in the pathogenesis of HPH.…”

Section: Discussionmentioning

confidence: 99%

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2

Wan

Yamamura

Zimnicka

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Hypoxia-induced pulmonary hypertension (HPH) is characterized by sustained pulmonary vasoconstriction and vascular remodeling, both of which are mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation, respectively. An increase in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ]cyt) is a major trigger for pulmonary vasoconstriction and an important stimulus for cell proliferation in PASMCs. Ca 2ϩ influx through voltage-dependent Ca 2ϩ channels (VDCC) is an important pathway for the regulation of [Ca 2ϩ ]cyt. The potential role for L-and T-type VDCC in the development of HPH is still unclear. Using a hypoxic-induced pulmonary hypertension mouse model, we undertook this study to identify if VDCC in pulmonary artery (PA) are functionally upregulated and determine which type of VDCC are altered in HPH. Mice subjected to chronic hypoxia developed pulmonary hypertension within 4 wk, and high-K ϩ -and U-46619-induced contraction of PA was greater in chronic hypoxic mice than that in normoxic control mice. Additionally, we demonstrate that high-K ϩ -and U-46619-induced Ca 2ϩ influx in PASMC is significantly increased in the hypoxic group. The VDCC activator, Bay K8864, induced greater contraction of the PA of hypoxic mice than in that of normoxic mice in isometric force measurements. L-type and T-type VDCC blockers significantly attenuated absolute contraction of the PA in hypoxic mice. Chronic hypoxia did not increase high-K ϩ -and U-46619-induced contraction of mesenteric artery (MA). Compared with MA, PA displayed higher expression of calcium channel voltagedependent L-type ␣ 1C-subunit (Cav1.2) and T-type ␣1H-subunit (Ca v3.2) upon exposure to chronic hypoxia. In conclusion, both L-type and T-type VDCC were functionally upregulated in PA, but not MA, in HPH mice, which could result from selectively increased expression of Ca v1.2 and Cav3.2.hypoxia; voltage-dependent calcium ion channel; pulmonary artery; mouse; calcium channel voltage-dependent L-type ␣ 1C-subunit; calcium channel voltage-dependent T-type ␣ 1H-subunit PERSISTENT HYPOXIA INDUCES vasoconstriction of small pulmonary arteries (PA) and vascular remodeling, including smooth muscle cell hypertrophy and hyperplasia, eventually resulting in hypoxic pulmonary hypertension (HPH). Pulmonary hypertension associated with hypoxia belongs to the third group in the classification of pulmonary hypertension according to the proceedings of the Fourth World Symposium on Pulmonary Hypertension at Dana Point 2008 (17). Over time, HPH causes right ventricle hypertrophy, right ventricular failure, and death (1, 37). Pulmonary hypertension related to chronic obstructive pulmonary disease (COPD) is one of the most common forms of HPH and is significantly associated with increased mortality (8, 36). Currently, there is no specific therapy for pulmonary hypertension associated with COPD, which provides motivation for researchers to understand the pathogenic mechanisms of HPH.Sustained pulmonary vasoconstriction and vascular remodeling are the predomina...

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Section: Discussionmentioning

confidence: 99%

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2

Wan

Yamamura

Zimnicka

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In fact, the DHP labeling could be increased by an increase in channel phosphorylation leading to membrane addressing as well as an increase in channel synthesis [27]. Of note that the use of the pharmacological detection of VDCC is more appropriate than the detection of CaV1.2 protein or RNA, since it has been shown recently that CaV1.2 subunits expression was not inevitably correlated with L-type current in VSMC [42].…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of ryanodine receptor expression increases the calcium-induced calcium release and spontaneous calcium signals in cerebral arteries from hindlimb unloaded rats

Morel

Dabertrand

Porte

et al. 2013

Pflugers Arch - Eur J Physiol

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Microgravity induces a redistribution of blood volume. Consequently, astronauts' body pressure is modified so that the upright blood pressure gradient is abolished, thereby inducing a modification in cerebral blood pressure. This effect is mimicked in the hindlimb unloaded rat model. After a duration of 8 days of unloading, Ca 2+ signals activated by depolarization and inositol-1,4,5-trisphosphate intracellular release were increased in cerebral arteries. In the presence of ryanodine and thapsigargin, the depolarization-induced Ca 2+ signals remained increased in hindlimb suspended animals, indicating that Ca 2+ influx and Ca 2+ -induced Ca 2+ release mechanism were both increased. Spontaneous Ca 2+ waves and localized Ca 2+ events were also investigated. Increases in both amplitude and frequency of spontaneous Ca 2+ waves were measured in hindlimb suspension conditions. After pharmacological segregation of Ca 2+ sparks and Ca 2+ sparklets, their kinetic parameters were characterized. Hindlimb suspension induced an increase in the frequencies of both Ca 2+ localized events, suggesting an increase of excitability. Labeling with bodipy compounds suggested that voltage-dependent Ca 2+ channels and ryanodine receptor expressions were increased. Finally, the expression of the ryanodine receptor subtype 1 (RyR1) was increased in hindlimb unloading conditions. Taken together, these results suggest that RyR1 expression and voltage-dependent Ca 2+ channels activity are the focal points of the regulation of Ca 2+ signals activated by vasoconstriction in rat cerebral arteries with an increase of the voltage-dependent Ca 2+ influx.

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“…Agonistinduced contractions were expressed as a percentage of the initial resting diameter (baseline) of the vessel. Agonist concentration producing EC 50 and maximum contraction (Emax) for NE and ET-1 were determined for each CRC fitted to a four-parameter logistic equation (OriginLab 8.0; OriginLab, Northampton, MA). The EC50 values are reported as pD2 values, which are the negative logarithm (Ϫlog) of the EC50 concentrations.…”

Section: ϫ11mentioning

confidence: 99%

“…Undoubtedly this is due, in no small part, to the significant technical challenges associated with studying the more delicate and thin-walled small veins and venules under conditions of distending pressure. Failure to detect venous myogenic tone in most experiments may be the result of vulnerability of the wall of the small veins (32).Alterations in VSM membrane potential and intracellular calcium levels cannot fully explain venous myogenic reactivity (33,45,50). In limited studies, inhibitors of PKC and Rho kinase, key regulatory molecules of VSM calcium sensitization, have been shown to abolish stretch-activated myogenic tone in rabbit facial veins using wire myography, but no studies have used pressurized vessels (8,27).…”

mentioning

confidence: 99%

“…Alterations in VSM membrane potential and intracellular calcium levels cannot fully explain venous myogenic reactivity (33,45,50). In limited studies, inhibitors of PKC and Rho kinase, key regulatory molecules of VSM calcium sensitization, have been shown to abolish stretch-activated myogenic tone in rabbit facial veins using wire myography, but no studies have used pressurized vessels (8,27).…”

mentioning

confidence: 99%

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Characteristics of myogenic reactivity in isolated rat mesenteric veins

Enouri¹,

Monteith

Johnson³

2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Enouri S, Monteith G, Johnson R. Characteristics of myogenic reactivity in isolated rat mesenteric veins. Am J Physiol Regul Integr Comp Physiol 300: R470 -R478, 2011. First published December 1, 2010; doi:10.1152/ajpregu.00491.2010.-Mechanisms of mechanically induced venous tone and its interaction with the endothelium and key vasoactive neurohormones are not well established. We investigated the contribution of the endothelium, L-type voltage-operated calcium channels (L-VOCCs), and PKC and Rho kinase to myogenic reactivity in mesenteric vessels exposed to increasing transmural pressure. The interaction of myogenic reactivity with norepinephrine (NE) and endothelin-1 (ET-1) was also investigated. Pressure myography was used to study isolated, cannulated, third-order rat mesenteric small veins and arteries. NE and ET-1 concentration response curves were constructed at low, intermediate, and high transmural pressures. Myogenic reactivity was not altered by nitric oxide synthase inhibition with N -nitro-L-arginine (L-NNA; 100 M) or endothelium removal in both vessels. L-VOCCs blockade (nifedipine, 1 M) completely abolished arterial tone, while only partially reducing venous tone. PKC (chelerythrine, 2.5 M) and Rho kinase (Y27632, 3 M) inhibitors largely abolished venous and arterial myogenic reactivity. There was no significant difference in the sensitivity of NE or ET-1-induced contractions within vessels. However, veins were more sensitive to NE and ET-1 when compared with corresponding arteries at low, intermediate, and high transmural pressures, respectively. These results suggest that 1) myogenic factors are important contributors to net venous tone in mesenteric veins; 2) PKC and Rho activation are important in myogenic reactivity in both vessels, while L-VOCCs play a limited role in the veins vs. the arteries, and the endothelium does not appear to modulate myogenic reactivity in either vessel type; and 3) mesenteric veins maintain an enhanced sensitivity to NE and ET-1 compared with the arteries when studied under conditions of changing transmural distending pressure. myogenic tone; myogenic responses; mesenteric small arteries; signal transduction; vasoactive agents THE PREVAILING LEVEL OF VASOMOTOR tone within a segment of the circulation is controlled primarily by sympathetic neurogenic influences, intrinsic myogenic properties of the vascular smooth muscle (VSM), and key local or circulating humoral factors (16,32,38). Varying contributions from these factors, in part, provide functional specialization of the veins vs. the arteries in a particular vascular bed while enabling the cardiovascular system to meet the changing demands of the body. Several studies conducted in veins including facial, saphenous, portal, skeletal muscle, and bat wing (3,6,7,15,18) have described myogenic tone in these vessels. However, the strength of myogenic tone varies between veins, being dependent on the function of the vascular bed and its contribution to venous capacitance. Pressure-induced myogenic tone in rat saphenou...

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Intracellular Ca ²⁺ Silences L-Type Ca ²⁺ Channels in Mesenteric Veins

Cited by 22 publications

References 53 publications

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2

Up-regulation of ryanodine receptor expression increases the calcium-induced calcium release and spontaneous calcium signals in cerebral arteries from hindlimb unloaded rats

Characteristics of myogenic reactivity in isolated rat mesenteric veins

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Intracellular Ca 2+ Silences L-Type Ca 2+ Channels in Mesenteric Veins

Cited by 22 publications

References 53 publications

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2

Up-regulation of ryanodine receptor expression increases the calcium-induced calcium release and spontaneous calcium signals in cerebral arteries from hindlimb unloaded rats

Characteristics of myogenic reactivity in isolated rat mesenteric veins

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Product

Resources

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Intracellular Ca ²⁺ Silences L-Type Ca ²⁺ Channels in Mesenteric Veins

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2

Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca²⁺ channel activity in pulmonary artery by upregulating Ca_v1.2 and Ca_v3.2