Endothelial and Smooth Muscle Cell Ion Channels in Pulmonary Vasoconstriction and Vascular Remodeling

Abstract

The pulmonary circulation is a low resistance and low pressure system. Sustained pulmonary vasoconstriction and excessive vascular remodeling often occur under pathophysiological conditions such as in patients with pulmonary hypertension. Pulmonary vasoconstriction is a consequence of smooth muscle contraction. Many factors released from the endothelium contribute to regulating pulmonary vascular tone, while the extracellular matrix in the adventitia is the major determinant of vascular wall compliance. Pulmonary vascular remodeling is characterized by adventitial and medial hypertrophy due to fibroblast and smooth muscle cell proliferation, neointimal proliferation, intimal, and plexiform lesions that obliterate the lumen, muscularization of precapillary arterioles, and in situ thrombosis. A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction, while increased release of mitogenic factors, upregulation (or downregulation) of ion channels and transporters, and abnormalities in intracellular signaling cascades are key to the remodeling of the pulmonary vasculature. Changes in the expression, function, and regulation of ion channels in PASMC and pulmonary arterial endothelial cells play an important role in the regulation of vascular tone and development of vascular remodeling. This article will focus on describing the ion channels and transporters that are involved in the regulation of pulmonary vascular function and structure and illustrating the potential pathogenic role of ion channels and transporters in the development of pulmonary vascular disease.

Pathogenic Role of Store-Operated and Receptor-Operated Ca2+ Channels in Pulmonary Arterial Hypertension

“…K + channels remain closed until stimulated to open, after stimulation, K + channels open causing membrane depolarization and leading to the opening of voltage-dependent Ca 2+ channels (VDCC) and contribute to increased levels of [Ca 2+ ] cyt causing vasoconstriction. However, when K + channels open this causes membrane depolarization, which closes VDCC, preventing the influx of Ca 2+ , leading to PASMC relaxation, and causing vasodilatation [35]. …”

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…Chloride channels (184, 303, 304, 584, 632, 829, 956, 957) and ENaC (340–342, 460, 502, 510, 698, 697, 1465) that may contribute to myogenic- and agonist-induced tone of some resistance arteries and arterioles will not be discussed. Ion channel function in the pulmonary circulation also will not be reviewed in detail (937). We will focus on ion channel function in establishing myogenic tone in resistance arteries and arterioles, the role played by these channels in the mechanism of action of vasodilators and vasoconstrictors that modulate vascular tone and the effects of disease states such as hypertension, obesity, and diabetes on ion channel expression and function.…”

Chronic Intermittent Hypobaric Hypoxia (4600 M) Attenuates Pulmonary Vasodilation Induced by Acetylcholine or Sodium Nitroprusside

“…The higher potassium R MAX values in intolerant rats could be explained by increased muscularization of the SPA. Pulmonary circulation is sensitive to the lack of oxygen, which promotes hypoxia pulmonary vasoconstriction and pathological remodeling which is characterized by pulmonary artery wall thickening (Makino et al, 2011). Studies have reported a direct relationship between R MAX and femoral artery muscle mass (Anwar et al, 2001) and a positive correlation between the maximum potassium response and vascular wall thickness (Pearce et al, 1991;Wagerle et al, 1995).…”

“…Increased potassium potency, observed in both intolerant and tolerant rats, suggests that CIHH increases the expression of contractile machinery stimulated by depolarization at lower potassium concentrations. According to the data in Table 1, the modified extracellular potassium concentration influences the electrochemical gradient and, according to the Nernst equation, predicts that the voltage threshold for contraction of the SPA of intolerant and tolerant rats is more negative than the control group (Papamatheakis et al, 2012;Makino et al, 2011;Jernigan and Resta, 2014). This contraction capacity at a lower potassium concentration could be explained by reduced expression of potassium channels in pulmonary arteries (i.e., Kv 1.2, Kv 1.5, and Kv 2.1) in rats exposed to chronic hypoxia (Wang et al, 2005;Whitman et al, 2008; and more detail see Sylvester et al, 2012); increased expression of the L and Ttype voltage-dependent calcium channel (Makino et al, 2011;Wan et al, 2013;Jernigan and Resta, 2014); and/or the coupled electro-mechano-contractile machinery present, similar to that described by Nauli et al (2005) who showed that Ca +2 had an increased capacity for promoting myosin phosphorylation in adult sheep basilar arteries during chronic hypoxia.…”