Brainstem activation of platelet-derived growth factor-beta receptor modulates the late phase of the hypoxic ventilatory response

The early phase of the biphasic ventilatory response to hypoxia in mammals is critically dependent on NMDA glutamate receptor activation within the nu cleus of the solitary tract. However, the mechanisms underlying the subsequ ent development of the typical ventilatory roll-off are unclear and could u nderlie important roles in the functional and molecular adaptation to oxyge n deprivation, Because the growth factor platelet-derived growth factor (PD GF)-BB can modulate the open channel probability of NMDA receptors by activ ating PDGF-beta receptors, its contribution to hypoxic ventilatory roll-off was examined. Administration of PDGF-BB, but not PDGF-AA, in the nucleus o f the solitary tract was associated with significant attenuations of the ea rly hypoxic ventilatory response in conscious rats. Furthermore, marked red uctions in the magnitude of hypoxic ventilatory roll-off occurred in mice h eterozygous for a mutation in the PDGF-beta receptor. Administration of a P DGF-beta receptor antagonist to wild-type littermates elicited similar decl ines in hypoxic ventilatory roll-off. The relative abundance of PDGF-beta r eceptors was confirmed in the nucleus of the solitary tract and other nucle i implicated in the hypoxic ventilatory response. In nucleus of the solitar y tract lysates, PDGF-beta receptor tyrosine phosphorylation was temporally correlated with hypoxic ventilatory roll-off formation. Increased PDGF-B c hain mRNA expression was induced by hypoxia in the nucleus of the solitary tract, and PDGF-B chain immunoreactivity colocalized with similar to 40% of nucleus of the solitary tract neurons, demonstrating hypoxia-induced c-Fos enhancements. Thus, PDGF-BB release and PDGF-beta receptor activation in t he nucleus of the solitary tract are critical components of hypoxic ventila tory roll-off and may have important functional implications in processes u nderlying survival and acclimatization to hypoxic environments.