A member of the tumor necrosis factor receptor family, p75-neurotrophin receptor (p75^NTR) has been previously shown to play a role in the regulation of fibrin deposition in the lung. However, the role of p75^NTR in the regulation of pulmonary vascular tone in the lung is unknown. In the current study, we evaluated the expression of p75^NTR in mouse pulmonary arteries, and the putative role of p75^NTR in modulating pulmonary vascular tone and agonist-responsiveness using wild-type (WT) and p75^NTR-knockout (p75^-/-) mice. Our data indicate that p75^NTR is 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 in comparison to 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, U46619 (a thromboxane A₂ analog), thrombin, 4-aminopyridine (a K⁺ channel blocker) and high extracellular K⁺ in p75^-/- rings was similar to that in WT rings. Deletion of p75^NTR did not alter pulmonary vasodilation to sodium nitroprusside (a nitric oxide donor). These data suggest that intact p75^NTR signaling may play a role in modulating pulmonary vasoconstriction induced by endothelin-1 and by active store depletion.