The Mechanism(s) of Hypoxic Pulmonary Vasoconstriction: Potassium Channels, Redox O2 Sensors, and Controversies

Physiology ◽  
2002 ◽  
Vol 17 (4) ◽  
pp. 131-137 ◽  
Author(s):  
Stephen Archer ◽  
Evangelos Michelakis
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Potassium Channels ◽  
Pulmonary Artery ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Artery Smooth Muscle

Hypoxic pulmonary vasoconstriction matches perfusion to ventilation and optimizes systemic oxygenation. Alterations in Po2 are sensed by a vascular redox O2 sensor in the pulmonary artery smooth muscle cell, probably within the mitochondria. This creates a signal that modulates redox-sensitive K+ channels, thereby controlling membrane potential, Ca2+ entry, and tone.

Pulmonary artery smooth muscle cell [Ca2+]i and contraction: responses to diphenyleneiodonium and hypoxia

1997 ◽  
Vol 273 (3) ◽  
pp. L603-L611 ◽  
Author(s):  
F. Zhang ◽  
R. C. Carson ◽  
H. Zhang ◽  
G. Gibson ◽  
H. M. Thomas
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Primary Cultures ◽  
Control Point ◽  
Collagen Gels ◽  
Potential Control ◽  
Pulmonary Artery Smooth Muscle

To investigate mechanisms of inhibition of hypoxic pulmonary vasoconstriction (HPV), we studied pulmonary artery smooth muscle cell (PASMC) responses to hypoxia, utilizing diphenyleneiodonium (DPI), which blocks HPV. We measured cell contraction in primary cultures of rat PASMC grown on collagen gels and cytosolic free Ca2+ concentration ([Ca2+]i) in PASMC grown on glass. DPI (5 and 20 microM) caused contraction of PASMC and increased [Ca2+]i. Omission of extracellular Ca2+ diminished the DPI-induced PASMC contraction and greatly reduced the increase in [Ca2+]i. DPI substantially inhibited KCl-induced PASMC contraction (1 microM DPI) and the increase in [Ca2+]i (5 microM DPI). Severe hypoxia contracted PASMC and quadrupled [Ca2+]i. DPI, 1 microM, substantially inhibited hypoxic contraction, but neither 1 nor 5 microM DPI diminished the hypoxia-induced increase in [Ca2+]i, which was greatly attenuated by 20 microM DPI. These data show 1) that DPI increases [Ca2+]i, accounting for DPI-induced PASMC contraction and 2) that 1 and 5 microM DPI inhibit the hypoxia-induced contraction but not the hypoxia-induced increase in [Ca2+]i, suggesting that DPI inhibits hypoxic PASMC contraction downstream of the Ca2+ signal by desensitizing the contractile apparatus and indicating a potential control point for modulation of HPV.

scholarly journals Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

2017 ◽  
Vol 42 (6) ◽  
pp. 2569-2581 ◽  
Author(s):  
Zengxian Sun ◽  
Xiaowei Nie ◽  
Shuyang Sun ◽  
Shumin Dong ◽  
Chunluan Yuan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Remodeling ◽  
Pulmonary Artery Smooth Muscle ◽  
And Migration ◽  
Proliferation And Migration

Background/Aims: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs) in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH) remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA–maternally expressed gene 3 (MEG3) was involved in PAH-related vascular remodeling. Methods: The arterial wall thickness was examined by hematoxylin and eosin (H&E) staining in distal pulmonary arteries (PAs) isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. Results: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G0/G1 phase to the G2/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3–induced smooth muscle cell proliferation. Conclusions: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH.

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