The aim of this study was to clarify the molecular mechanisms of hypoxic pulmonary
vasoconstriction in precapillary arterial pulmonary smooth muscle cells (PASMC) and
ischemia-reperfusion injury in lung endothelial cells (LEC). TRPC6-activation is
essential for both mechanisms, because they are abolished in TRPC6-deficient mice.
To investigate the mechanisms at the cellular level PASMC and LEC were isolated
and their identity confirmed by specific antibodies. Components of the signalling
cascade in both cell types were identified by monitoring the Ca2+-increase in
response to the application of hypoxic solutions. Important key components of the
signal transduction cascades in addition to TRPC6 were identified by the application
of specific inhibitors and sensors to the cells. In summary, activation of receptors by
nanomolar agonist concentrations (priming) results in a low level of diacylglycerol
(DAG) production, which is not able to activate TRPC6 channels, but is rapidly
degraded by DAG-kinases. After application of hypoxia, however, production of
reactive oxygen species results in DAG-kinase inhibition and sufficient DAGaccumulation
to induce TRPC6-activation. The bulk of Ca2+ influx in PASMC
responsible for contraction enters through L-type voltage gated Ca2+ channels. These
are activated by the depolarisation resulting from Na+ influx through TRPC6-
channels. A similar signal transduction cascade exists in LEC, although it is unclear
whether a priming event is necessary. In these cells, TRPC6 channels mediate the
Ca2+ influx, because L-type voltage gated calcium channels are not expressed.
Therefore, TRPC6 is an important perspective pharmacological target for acute
hypoxic pulmonary vasoconstriction in PASMC and ischemia-reperfusion injury in
LEC.
Kalwa, Hermann: Die physiologische Funktion von TRPC6 in Endothelzellen und glatten Muskelzellen der Lunge. : Philipps-Universität Marburg 2009-10-08. DOI: https://doi.org/10.17192/z2009.0514.
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