Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6

Background: Hypoxic pulmonary vasoconstriction (HPV) is an
essential mechanism of the lung that matches blood perfusion to
alveolar ventilation to optimize gas exchange. Recently we have
demonstrated that acute but not sustained HPV is critically
dependent on the classical transient receptor potential 6 (TRPC6)
channel. However, the mechanism of TRPC6 activation during acute
HPV remains elusive. We hypothesize that a diacylglycerol
(DAG)-dependent activation of TRPC6 regulates acute HPV. Methods:
We investigated the effect of the DAG analog
1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in
isolated perfused and ventilated mouse lungs from TRPC6-deficient
and wild-type mice. Moreover, the effects of OAG, the DAG kinase
inhibitor R59949 and the phospholipase C inhibitor U73122 on the
strength of HPV were investigated compared to those on
non-hypoxia-induced vasoconstriction elicited by the thromboxane
mimeticum U46619. Results: OAG increased normoxic vascular tone in
lungs from wild-type mice, but not in lungs from TRPC6-deficient
mice. Under conditions of repetitive hypoxic ventilation, OAG as
well as R59949 dose-dependently attenuated the strength of acute
HPV whereas U46619-induced vasoconstrictions were not reduced. Like
OAG, R59949 mimicked HPV, since it induced a dose-dependent
vasoconstriction during normoxic ventilation. In contrast, U73122,
a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the
inactive form of U73122, had no effect on HPV. Conclusion: These
findings support the conclusion that the TRPC6-dependency of acute
HPV is induced via DAG.