Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 304, Issue 11, Pages C1042-C1052Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00304.2012
Keywords
vascular contraction; reactive oxygen species; pulmonary arterial smooth muscle
Categories
Funding
- National Heart, Lung, and Blood Institute [HL-115014, HL-066012, HL-098053]
- National Natural Science Foundation of China [81228001, 81270117, 30810103904]
- Grants-in-Aid for Scientific Research [25460104, 23790092, 25860068] Funding Source: KAKEN
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Electromechanical coupling via membrane depolarization-mediated activation of voltage-dependent Ca2+ channels (VDCC) is an important mechanism in regulating pulmonary vascular tone, while mouse is an animal model often used to study pathogenic mechanisms of pulmonary vascular disease. The function of VDCC in mouse pulmonary artery (PA) smooth muscle cells (PASMC), however, has not been characterized, and their functional role in reactive oxygen species (ROS)-mediated regulation of vascular function remains unclear. In this study, we characterized the electrophysiological and pharmacological properties of VDCC in PASMC and the divergent effects of ROS produced by xanthine oxidase (XO) and hypoxanthine (HX) on VDCC in PA and mesenteric artery (MA). Our data show that removal of extracellular Ca2+ or application of nifedipine, a dihydropyridine VDCC blocker, both significantly inhibited 80 mM K+-mediated PA contraction. In freshly dissociated PASMC, the maximum inward Ca2+ currents were -2.6 +/- 0.2 pA/pF at +10 mV (with a holding potential of -70 mV). Window currents were between -40 and +10 mV with a peak at -15.4 mV. Nifedipine inhibited currents with an IC50 of 0.023 mu M, and 1 mu M Bay K8644, a dihydropyridine VDCC agonist, increased the inward currents by 61%. XO/HX attenuated 60 mM K+-mediated increase in cytosolic free Ca2+ concentration ([Ca2+](cyt)) due to Ca2+ influx through VDCC in PASMC. Exposure to XO/HX caused relaxation in PA preconstricted by 80 mM K+ but not in aorta and MA. In contrast, H2O2 inhibited high K+ -mediated increase in [Ca2(+)] cyt and caused relaxation in both PA and MA. Indeed, RT-PCR and Western blot analysis revealed significantly lower expression of Ca-V 1.3 in MA compared with PA. Thus our study characterized the properties of VDCC and demonstrates that ROS differentially regulate vascular contraction by regulating VDCC in PA and systemic arteries.
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