Heterogeneity of hypoxia-mediated decrease inIK(V)and increase in [Ca2+]cytin pulmonary artery smooth muscle cells

Platoshyn, Oleksandr; Yu, Ying; Ko, Eun A.; Remillard, Carmelle V.; Yuan, Jason X.‐J.

doi:10.1152/ajplung.00391.2006

Cited by 33 publications

(34 citation statements)

References 93 publications

(168 reference statements)

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“…It is noteworthy that these calcium signal time courses are similar to those we reported in rat pulmonary arteries [5]. In freshly dissociated or cultured smooth muscle cells from the same segment of rat pulmonary arteries, different smooth muscle cell phenotypes have been shown to correlate with the activity of different potassium channels [22] or different profiles of Ca 2+ responses to hypoxia or ATP, which mobilises intracellular calcium via G protein receptor activation [23]. The various patterns of calcium responses to 5-HT observed in the present study may, therefore, be related to different PASMC phenotypes which might relate to their physiological status.…”

Section: Effect Of 5-ht On Casupporting

confidence: 80%

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Rodat-Despoix¹,

Aires²,

Ducret³

et al. 2009

Eur Respir J

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Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose plasma level is increased in pulmonary hypertensive patients. Thus, we explored the signalling pathways involved in the contractile response to 5-HT in human pulmonary arteries (HPAs).Intact and b-escin permeabilised rings from HPAs mounted in an organ bath system were used to assess both tension and myofilament Ca 2+ -sensitisation. KEYWORDS: Calcium, contraction, human pulmonary artery, myofilament calcium sensitivity, 5-HT S erotonin (5-hydroxytryptamine; 5-HT) is mainly stored in the platelets but is also locally released in the lung by pulmonary neuroendocrine cells, neuroepithelial bodies and pulmonary arterial endothelial cells [1][2][3]. 5-HT is a potent pulmonary vasoconstrictor whose high circulating concentration is clinically associated with pulmonary arterial hypertension (PAH), an often fatal disease. In animal models of PAH, 5-HT-induced hyperreactivity and mitogenic effects have been reported in pulmonary arteries [4,5]. In human pulmonary arteries (HPAs), while numerous studies have explored the role of 5-HT in vascular remodelling associated with smooth muscle hyperplasia [6,7], few studies have been performed on the contractile effect of 5-HT [8,9]. Nevertheless, 5-HT 1B , 5-HT 2A and 5-HT 2B receptors have been detected in HPA, and the contractile effect of 5-HT appeared to be mainly mediated by the 5-HT 1B receptors and also by the 5-HT 2A receptors [6,[8][9][10][11][12]. Despite the fact that pulmonary arterial vasoconstriction is an important early component of PAH, the current knowledge about transduction pathways involved in the 5-HTinduced vasoreactivity remains incomplete for HPAs.Owing to the low availability of human tissue, we previously studied the contractile response to 5-HT in rat intrapulmonary arteries and we demonstrated that there were regional differences in 5-HT-induced contraction [13]. Since calcium is essential for smooth muscle contraction, we addressed the relative contribution of calcium pools involved in the vasoreactivity to 5-HT. In small vessels, 5-HT activates voltage-independent calcium channels to a larger extent than it does voltage-dependent calcium channels (L-type calcium channels) [5,[13][14][15]. Calcium release from intracellular calcium stores (sarcoplasmic reticulum) also contributes to 5-HT-induced contraction in rat pulmonary arteries [13][14][15]. Studies from other groups have been performed on calcium signalling and ion channels in cultured human

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Section: Effect Of 5-ht On Casupporting

confidence: 80%

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Rodat-Despoix¹,

Aires²,

Ducret³

et al. 2009

Eur Respir J

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“…In PASMCs, hypoxia-induced membrane depolarization has been attributed to the inhibition of oxygen-sensitive, voltagegated K + (K v ) channels, of which K v 1.5 and K v 2.1 are considered particularly relevant (20)(21)(22). To test the potential involvement of these channels in the hypoxic response of lung microvascular endothelial cells, we determined their expression and functionality in the intact mouse lung preparation.…”

Section: Cx40 Deficiency Attenuates Chronic Hypoxic Pulmonary Hypertementioning

confidence: 99%

Hypoxic pulmonary vasoconstriction requires connexin 40–mediated endothelial signal conduction

Wang¹,

Yin²,

Nickles³

et al. 2012

J. Clin. Invest.

133

120

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Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which pulmonary arteries constrict in hypoxic lung areas in order to redirect blood flow to areas with greater oxygen supply. Both oxygen sensing and the contractile response are thought to be intrinsic to pulmonary arterial smooth muscle cells. Here we speculated that the ideal site for oxygen sensing might instead be at the alveolocapillary level, with subsequent retrograde propagation to upstream arterioles via connexin 40 (Cx40) endothelial gap junctions. HPV was largely attenuated by Cx40-specific and nonspecific gap junction uncouplers in the lungs of wildtype mice and in lungs from mice lacking Cx40 (Cx40 -/-). In vivo, hypoxemia was more severe in Cx40 -/-mice than in wild-type mice. Real-time fluorescence imaging revealed that hypoxia caused endothelial membrane depolarization in alveolar capillaries that propagated to upstream arterioles in wild-type, but not Cx40 -/-, mice. Transformation of endothelial depolarization into vasoconstriction involved endothelial voltage-dependent α 1G subtype Ca 2+ channels, cytosolic phospholipase A 2 , and epoxyeicosatrienoic acids. Based on these data, we propose that HPV originates at the alveolocapillary level, from which the hypoxic signal is propagated as endothelial membrane depolarization to upstream arterioles in a Cx40-dependent manner. IntroductionHypoxic pulmonary vasoconstriction (HPV) is a fundamental physiological mechanism by which the lung optimizes ventilation/ perfusion (V/Q) matching, redirecting blood flow from poorly to better ventilated areas (1). Yet in cases of global hypoxia, HPV may unfavorably increase total pulmonary vascular resistance and right ventricular afterload, thus contributing to the clinical pathology of pulmonary hypertension and cor pulmonale in chronic hypoxic lung diseases or to pulmonary edema at high altitude (1, 2). While the relevance of HPV has been recognized for over 60 years, the underlying oxygen sensing and signal transduction processes remain a topic of intense research and controversy. Current concepts of HPV are largely based on the notion that pulmonary arterial smooth muscle cells (PASMCs) constitute both the sensor and the transducer of the hypoxic signal as well as its contractile effector (1), while the role of the vascular endothelium is at best considered that of a modulating bystander.From a conceptual standpoint, the ideal site for an oxygen sensor in HPV is within the actual area of pulmonary gas exchange,

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“…24,25) However, it remains unclear whether these changes in Kv function and expression are etiologically linked to HA-PAH. The reduction of Kv channel activity and the subsequent membrane depolarization appear to be involved in the development of chronic pulmonary hypertension by mediating pulmonary vasoconstriction and vascular remodeling through an increase of [Ca 2+ ]i, 3,4,26) which suggests that PA remodeling is correlated with [Ca 2+ ]i. We showed that the [Ca 2+ ]i increased in the PAs of HA rats, which may be the mechanism underlying the specific Kv channel that mediates HA-PAH.…”

Section: Discussionmentioning

confidence: 61%

“…3,4,33) Our study indicates that DCA could inhibit the proliferation of PASMCs by up-regulating Kv channels and reducing ([Ca 2+ ]i). DCA enhances apoptosis in monocrotaline-induced PAH by increasing H 2 O 2 production.…”

Section: Discussionmentioning

confidence: 72%

“…Both the contractile and proliferative status of SMCs are regulated by the level of intracellular Ca 2+ ([Ca 2+ ]i). 3,4) Hypoxia causes a rapid and reversible increase in [Ca 2+ ]i, which leads to SMC contraction and proliferation. [Ca 2+ ]i is determined in part by the influx of Ca 2+ through voltage-gated, L-type Ca 2+ channels, 5,6) which are gated based on the membrane potential (Em) of the SMCs.…”

Section: Introductionmentioning

confidence: 99%

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Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

Peng

Sun

et al. 2011

JOURNAL OF HEALTH SCIENCE

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To investigate the effect of dichloroacetate (DCA) on the mean pulmonary artery pressure (mPAP), pulmonary artery (PA) remodeling and voltage-gate K + (Kv) channel expression in pulmonary arterial smooth muscle cells (PASMCs) in high altitude-induced pulmonary artery hypertension (HA-PAH) rats. Sprague-Dawley rats were randomly assigned to normal control (N), high altitude (HA), and HA+DCA (70 mg/kg DCA administration daily) groups (n = 8 each). Rats were housed in a hypobaric, hypoxic chamber to mimic an altitude of 5000 m for 21 days; then the mPAP and the wall thickness (WT) of the PA smooth muscle were measured. PASMCs apoptosis was examined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stain. Real-time PCR, immunohistochemistry and western blot analyses were carried out to detect Kv1.5 and Kv2.1 expression in PASMCs. The expression of Kv1.5 and Kv2.1 was decreased in HA rats. With DCA treatment, the expression of Kv1.5 and Kv2.1 was restored, and the established HA-PAH was ameliorated. Compared with the HA-PAH rats, the DCA-treated rats displayed a decreased mPAP, WT of the PAs, right ventricular hypertrophy and ([Ca 2+ ]i), and more PASMCs were apoptotic. DCA partially reversed the down-regulation of Kv1.5 and Kv2.1 in the PASMCs of HA-PAH rats. DCA can reverse the remodeling of the PA and upregulate Kv1.5 and Kv2.1 expression in the PASMCs of HA-PAH rats. This result suggests that DCA may be an effective drug for treating HA-PAH and that restoring Kv1.5 and Kv2.1 can partially decrease mPAP.

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Heterogeneity of hypoxia-mediated decrease inI_K(V)and increase in [Ca²⁺]_cytin pulmonary artery smooth muscle cells

Cited by 33 publications

References 93 publications

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Hypoxic pulmonary vasoconstriction requires connexin 40–mediated endothelial signal conduction

Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

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