p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction

Abstract

JXJ. p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction. Am J Physiol Heart Circ Physiol 295: H1529-H1538, 2008. First published August 8, 2008 doi:10.1152/ajpheart.00115.2008.-A member of the TNF receptor family, the 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 present 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 Ϫ/Ϫ ) mice. Our data indicated 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 Ϫ/Ϫ mice exhibited significantly elevated active tension due to endothelin-1-mediated Ca 2ϩ influx. Furthermore, the contraction due to capacitative Ca 2ϩ entry (CCE) in response to phenylephrine-mediated active depletion of intracellular Ca 2ϩ 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 Ϫ/Ϫ rings. Active tension induced by serotonin, U-46619 (a thromboxane A 2 analog), thrombin, 4-aminopyridine (a K ϩ channel blocker), and high extracellular K ϩ in p75 Ϫ/Ϫ 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. mouse; pulmonary artery; pharmacology; vasoconstriction; store depletion NEUROTROPHINS are unique growth factors that interact with two separate types of transmembrane receptors: tropomyosin receptor kinases (Trk) and the p75 neurotrophin receptor (p75 NTR ), with the latter being a member of the TNF superfamily of membrane receptors (38). A wealth of in vitro experiments has shown that neurotrophins and pro-neurotrophins can induce apoptosis via p75 NTR (15). In vivo, p75 NTR expression and induction are associated with increased apoptosis in vascular smooth muscle cells (SMCs) from atherosclerotic lesions (15, 41) as well as in promoting apoptosis in oligodendrocytes and neurons in injury models in the nervous system (1, 2, 26). Conversely, Chu et al. (9)

Neurotrophins in lung health and disease

“…There is now some evidence that NT signaling may be important in the control of vascular structure and function [37,80–84]. In extrapulmonary branches of the human pulmonary artery, immunocytochemical studies show that NGF, BDNF and NT3 are present at comparable levels, particularly in the intima as well as the adventitia (with some reactivity in the inner layer of the smooth muscle media) [84].…”

“…Furthermore, in human pulmonary artery rings, these NTs induce acute vasodilation that is blunted by removal of the endothelium. In mouse pulmonary arteries, the low-affinity p75NTR receptor is expressed in both the endothelium and smooth muscle [80]. Furthermore, pulmonary artery rings from p75NTR knockout mice show significantly elevated contractions in response to endothelin-1 (but not other constrictors, suggesting the involvement of specific Ca 2+ regulatory mechanisms).…”

Expression and Role of the TrkA Receptor in Pulmonary Inflammatory Diseases

“…Neurotrophins and their receptors are expressed on pulmonary arteries (Ricci et al, 2000a), and their expression is increased in the lung of spontaneously hypertensive rats (Ricci et al, 2004a). A role for neurotrophins in the control of the pulmonary arterial tone was recently proposed, through activation of the p75 NTR receptor (Xu et al, 2008). BDNF and NT-3 induce relaxation of porcine pulmonary arterial rings, through activation of the endothelial nitric oxide synthase (Meuchel et al, 2011).…”

Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle

“…Overall, these data point to a complex role of locally-produced BDNF within the PA that may detrimentally or beneficially influence arterial contractility and relaxation in a context-sensitive fashion. A single study in pulmonary artery rings from p75NTR knockout mice showed increased contractions to endothelin-1[ 64 ] suggesting a vasodilatory role for neurotrophins, however such an effect cannot be attributed to BDNF (p75NTR is activated by all neurotrophins), to TrkB, or to PASMCs. Furthermore, it is likely that long-term lack of p75NTR could have a completely different effect on vascular structure and function.…”