title: Brainstem activation of platelet-derived growth factor-beta receptor modulates the late phase of the hypoxic ventilatory response.
abstract: The early phase of the biphasic ventilatory response to hypoxia in mammals is critically dependent on NMDA glutamate receptor activation within the nucleus of the solitary tract. However, the mechanisms underlying the subsequent development of the typical ventilatory roll-off are unclear and could underlie important roles in the functional and molecular adaptation to oxygen deprivation. Because the growth factor platelet-derived growth factor (PDGF)-BB can modulate the open channel probability of NMDA receptors by activating PDGF-beta receptors, its contribution to hypoxic ventilatory roll-off was examined. Administration of PDGF-BB, but not PDGF-AA, in the nucleus of the solitary tract was associated with significant attenuations of the early hypoxic ventilatory response in conscious rats. Furthermore, marked reductions in the magnitude of hypoxic ventilatory roll-off occurred in mice heterozygous for a mutation in the PDGF-beta receptor. Administration of a PDGF-beta receptor antagonist to wild-type littermates elicited similar declines in hypoxic ventilatory roll-off. The relative abundance of PDGF-beta receptors was confirmed in the nucleus of the solitary tract and other nuclei implicated in the hypoxic ventilatory response. In nucleus of the solitary tract lysates, PDGF-beta receptor tyrosine phosphorylation was temporally correlated with hypoxic ventilatory roll-off formation. Increased PDGF-B chain mRNA expression was induced by hypoxia in the nucleus of the solitary tract, and PDGF-B chain immunoreactivity colocalized with approximately 40% of nucleus of the solitary tract neurons, demonstrating hypoxia-induced c-Fos enhancements. Thus, PDGF-BB release and PDGF-beta receptor activation in the nucleus of the solitary tract are critical components of hypoxic ventilatory roll-off and may have important functional implications in processes underlying survival and acclimatization to hypoxic environments.
authors.affiliation: Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA. d0goza01@gwise.louisville.edu
authors.forename: D
authors.initials: D
authors.lastname: Gozal
authors.forename: N
authors.initials: N
authors.lastname: Simakajornboon
authors.forename: M A
authors.initials: MA
authors.lastname: Czapla
authors.forename: Y D
authors.initials: YD
authors.lastname: Xue
authors.forename: E
authors.initials: E
authors.lastname: Gozal
authors.forename: V
authors.initials: V
authors.lastname: Vlasic
authors.forename: J A
authors.initials: JA
authors.lastname: Lasky
authors.forename: J Y
authors.initials: JY
authors.lastname: Liu
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001933:Brain Stem / Q000378:metabolism*; D000860:Hypoxia / Q000503:physiopathology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice / Q000235:genetics; D009154:Mutation / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011233:Precipitin Tests; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000502:physiology*; D012119:Respiration; D017552:Solitary Nucleus / Q000378:metabolism / Q000502:physiology
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta