p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction

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Abstract
A member of the TNF receptor family, the p75 neurotrophin receptor (p75NTR) has been previously shown to play a role in the regulation of fibrin deposition in the lung. However, the role of p75NTRin the regulation of pulmonary vascular tone in the lung is unknown. In the present study, we evaluated the expression of p75NTRin mouse pulmonary arteries and the putative role of p75NTRin modulating pulmonary vascular tone and agonist responsiveness using wild-type (WT) and p75NTRknockout (p75−/−) mice. Our data indicated that p75NTRis expressed in both smooth muscle and endothelial cells within the pulmonary vascular wall in WT mice. Pulmonary artery rings from p75−/−mice exhibited significantly elevated active tension due to endothelin-1-mediated Ca2+influx. Furthermore, the contraction due to capacitative Ca2+entry (CCE) in response to phenylephrine-mediated active depletion of intracellular Ca2+stores was significantly enhanced compared with WT rings. The contraction due to CCE induced by passive store depletion, however, was comparable between WT and p75−/−rings. Active tension induced by serotonin, U-46619 (a thromboxane A2analog), thrombin, 4-aminopyridine (a K+channel blocker), and high extracellular K+in p75−/−rings was similar to that in WT rings. Deletion of p75NTRdid not alter pulmonary vasodilation to sodium nitroprusside (a nitric oxide donor). These data suggest that intact p75NTRsignaling may play a role in modulating pulmonary vasoconstriction induced by endothelin-1 and by active store depletion.