High altitude pulmonary hypertension: role of K+ and Ca2+ channels - PubMed (original) (raw)

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High altitude pulmonary hypertension: role of K+ and Ca2+ channels

Carmelle V Remillard et al. High Alt Med Biol. 2005 Summer.

Abstract

Global alveolar hypoxia, as experienced at high-altitude living, has a serious impact on vascular physiology, particularly on the pulmonary vasculature. The effects of sustained hypoxia on pulmonary arteries include sustained vasoconstriction and enhanced medial hypertrophy. As the major component of the vascular media, pulmonary artery smooth muscle cells (PASMC) are the main effectors of the physiological response(s) induced during or following hypoxic exposure. Endothelial cells, on the other hand, can sense humoral and hemodynamic changes incurred by hypoxia, triggering their production of vasoactive and mitogenic factors that then alter PASMC function and growth. Transmembrane ion flux through channels in the plasma membrane not only modulates excitation- contraction coupling in PASMC, but also regulates cell volume, apoptosis, and proliferation. In this review, we examine the roles of K+ and Ca2+ channels in the pulmonary vasoconstriction and vascular remodeling observed during chronic hypoxia-induced pulmonary hypertension.

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Figures

Figure. 1

Figure. 1

Geometric and morphological changes induced by chronic hypoxia. (A) Diagram depicting hypoxia-induced vasoconstriction and vascular remodeling in pulmonary arteries (PA). Both vasoconstriction (B) and medial hypertrophy (C) are clearly demonstrated in an X-ray image (B) and lung histological preparations (C). Images in B and C are reproduced with permission from (Dawson, 2004) and (Michelakis et al., 2002), respectively.

Figure 2

Figure 2

Effect of sustained hypoxia on K+ channel gene transcription (A), gene expression (B), Kv currents (C), membrane potential (D), resting [Ca2+]cyt (E), and concomitant effects on both pulmonary vascular tone (F) and remodeling (G). In panels B-E inclusively, effects of hypoxia are shown in the unboxed images on the right. TF, transcription factor.

Figure 3

Figure 3

[K+]cyt flux influences apoptosis. Normally, the high level of cytoplasmic K+ ([K+]cyt) contributes to maintaining cell volume and suppresses (−) cytoplasmic caspase activity, thereby inhibiting the onset of apoptotic cell shrinkage and the apoptotic cascade. Opening or upregulation of K+ channels would accelerate (+) apoptotic volume decrease and enhance apoptosis by increasing K+ efflux and loss.

Figure 4

Figure 4

Effect of chronic hypoxia on TRPC channel expression and function in PASMC (A-B) and PAEC (C-E) in the modulation of pulmonary vascular tone and medial hypertrophy. Panels A and C describe the effects of sustained hypoxia on TRPC expression in PASMC and PAEC, respectively. Effects of hypoxia on _I_SOC and CCE are shown in panels B and D for both preparations. In PASMC, enhanced TRPC expression and CCE lead to increased PASMC contraction and proliferation. In PAEC, increased CCE enhances Ca2+-dependent AP-1 binding activity (E), thereby promoting the transcription of mitogens and growth factors such as ET-1 and PDGF, which stimulate PASMC contraction and proliferation via paracrine interactions with their respective G protein-coupled receptor (GPCR) and receptor tyrosine kinase (RTK) on PASMC membranes. Traces in panels B and D are reproduced with permission from (Lin et al., 2004) and (Fantozzi et al., 2003), respectively.

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