Objectives: 

Despite intensive research, the molecular basis of hypoxic pulmonary vasoconstriction (HPV) remains one of the most enduring mysteries of cell physiology. Herein I summarize the work we made in recent years about the role of neutral sphingomyelinase (nSMase) and protein kinase C zeta in hypoxic pulmonary vasoconstriction and in the vasoconstriction induced by oxygen in the ductus arteriosus. We have also analyzed the role of nSMase in pulmonary hypertension and in the uncoupling of HPV characteristic of acute pulmonary injury.

Materials: 

Vasoconstriction was analyzed in isolated arteries mounted in a myograph in vitro and the HPV was also recorded in vivo.

Results: 

We found that hypoxia increased ceramide content which was abrogated by inhibition of nSMase. The hypoxia-induced vasoconstrictor response in isolated small pulmonary arteries was strongly reduced by inhibition of PKCzeta or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo in anesthetized open-chest rats. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of SMase or ceramide. This response was specific of pulmonary arteries, i.e. in mesenteric arteries hypoxia failed to increase ceramide. Inhibition of nSMase also prevented the vasosonctriction induced by oxygen in the ductus arteriosus and this latter response was mimicked by ceramide. In both the pulmonary arteries and the ductus arteriosus, ceramide increased the production of reactive oxygen species and inhibited voltage-dependent potassium channels (Kv).

Conclusions: 

nSMase-derived ceramide production and the activation of PKCzeta are early and necessary events in the signaling cascade of HPV and oxygen-induced ductal vasoconstriction. These novel and specific mechanisms of vasoconstriction involve protein kinase C zeta, NADPH oxidase derived reactive oxygen species and blockade of Kv chanels.