The influence of gap junction network complexity on pulmonary artery smooth muscle reactivity in normoxic and chronically hypoxic conditions

Abstract

New Findings r What is the central question of this study?Experimental results on intrapulmonary arteries indicate that the relationship between gap junctional intercellular communication and its functional involvement in tissue reactivity is very complex, both in normoxic and in chronically hypoxic conditions. The relationship between the gap junction network and vasoreactivity is poorly known and needs to be explored, including theoretical modelling approaches. r What is the main finding and its importance?Our results indicate that the role of gap junctions and their contribution to intrapulmonary artery reactivity depends crucially on the topology of the gap junctional communication network. In normoxia, myocytes are connected in a complex network, whereas chronic hypoxia is related to loss of the network complexity, leading to hypersensitivity.Experiments on intrapulmonary arteries (IPAs) isolated from rats maintained in normoxia and chronic hypobaric hypoxia showed that in normoxia, the IPA contractile sensitivity to KCl was not modified by gap junction inhibition. In contrast, chronic hypoxia induced an endothelium-independent hypersensitivity, which was suppressed by gap junction inhibition. For the theoretical analysis of these results, we developed a model of interconnected myocytes. Given that smooth muscle cells in IPAs are known to communicate via gap junctions, we regard the cytoarchitecture of the IPA as a spatial network, in which nodes represent individual smooth muscle cells and the links signify intercellular communication. A single-cell model that drives the dynamics of individual nodes includes the major elements of voltage-dependent Ca 2+ signalling. In addition, interindividual variability of SMCs is introduced by distributing the reversal potentials for K + . Cell-to-cell connection consists of passive Ca 2+ diffusion and electrical coupling, and connection between cells is determined by the topology of the intercellular network. Model predictions indicate that the experimental results can be explained by topological modifications and not by changes in the number of gap junctions. According to the model, in normoxia the myocytes are connected in a complex network, whereas chronic hypoxia is related to loss of complexity, leading to hypersensitivity. Our results thus indicate that chronic

Connexins in the control of vasomotor function

“…175 Studies in mice demonstrated that chronic exposure to hypoxia increased the pulmonary arterial constriction induced by depolarizing high potassium solutions. 176,177 This increased potassium sensitivity could be prevented by gap junction inhibitors. A very interesting mathematical model developed on the basis of these findings suggests that not the number of gap junctions per se, but differences in their arrangement could explain this behaviour.…”

“…A reduction of the complexity of smooth muscle interactions, possibly induced by hypoxia, might increase the constrictor response of the pulmonary vascular wall since single, "overreacting" cells might act then as effective pacemakers. 177 Gap junctional communication between smooth muscle cells can also lead to conducted responses. In smooth muscle, both smooth muscle-conducted constriction and dilation in response to local application of high potassium or adenosine have been described by de Wit.…”

Patterns of endothelium-dependent circulation reactions development in patients with ischemic stroke in case of oxigenation disturbances

“…Таким образом, при хронической гипоксии, хотя уровень NO 2 и NO 3 в плазме крови остаётся выше, усиленное образование эндотелина-1 при ХГГ стимулирует образование свободных радикалов кислорода [2,9], тормозящих реализацию NO своих вазодилатационных влияний на гладкомышечные клетки сосудистой стенки. Это приводит к нарушению равновесия вазоконстриктивных и вазодилатационных влияний со стороны эндотелия на тонус сосудов с доминированием вазоконстриктивных, прежде всего в результате повышенного уровня эндотелина-1 при хронической гипоксии.…”

Involvement of gap junctions between smooth muscle cells in sustained hypoxic pulmonary vasoconstriction development: a potential role for 15-HETE and 20-HETE

“…The electrical and biochemical properties of gap junction channels are regulated by phosphorylation and dephosphorylation of Cxs (12). It has been shown that GJs in pulmonary vascular wall are important for its remodeling and reactivity changes under chronic hypoxia (5,22) and MEGJs are involved in the sustained HPV development in rodent models (30,49). However, such a contribution of GJs to the sustained HPV phase in BIPAs is not yet reported.…”