Brainstem Activation of Platelet‐Derived Growth Factor‐β Receptor Modulates the Late Phase of the Hypoxic Ventilatory Response

Abstract

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 plateletderived growth factor (PDGF)-BB can modulate the open channel probability of NMDA receptors by activating PDGF-␤ 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-␤ receptor. Administration of a PDGF-␤ receptor antagonist to wild-type littermates elicited similar declines in hypoxic ventilatory roll-off. The relative abundance of PDGF-␤ 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-␤ 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 ϳ40% of nucleus of the solitary tract neurons, demonstrating hypoxia-induced c-Fos enhancements. Thus, PDGF-BB release and PDGF-␤ 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.

Hypoxic Ventilatory Response in Platelet-Derived Growth Factor Receptor-β–Knockout Mice

“…It is thought that PDGF-BB is released and accumulates along with the period of hypoxic challenge, and its concentration is sufficient for being effective during the late hypoxic phase but not enough during the initial phase. This is also parallel to the evidence that hypoxia increased the content of PDGF-B chain mRNA and PDGFR-β expression in the NTS in a timedependent manner (8).…”

“…This is consistent with the result demonstrated by Gozal et al using mice heterozygous for a mutation in PDGFR-β (8) and agrees with their suggestion that PDGFR-β-mediated mechanisms modulate the late decline of hypoxic ventilation. That the response was confined to the late phase of hypoxia may be explained by the delayed onset of PDGF-BB action because administration of an antagonist of PBGF-BB, CGP 57148B, attenuated only the late hypoxic decline in mice (8). It is thought that PDGF-BB is released and accumulates along with the period of hypoxic challenge, and its concentration is sufficient for being effective during the late hypoxic phase but not enough during the initial phase.…”

“…The most important finding obtained in the present study is that blockade of NMDA receptors eliminated the attenuation of the late decline observed in KO mice and hence the hypoxic ventilatory response became similar in WT and KO mice. PDGF-BB is abundantly expressed in the NTS (8,28), and sustained hypoxic stimulation induces the release of PDGF-BB and activates PDGFR-β in the NTS (8,29,30). Therefore, it is possible that during hypoxia the activation of PDGFR-β by endogenously released PDGF-BB effectively inhibits the NMDA receptors.…”

“…Gozal and coworkers (8) have presented interesting results that the hypoxic ventilatory response in rats is inhibited by microinjection of platelet-derived growth factor (PDGF)-BB, but not PDGF-AA, into the dorsocaudal brainstem, which activates the PDGF receptor (PDGFR)-β. Moreover, marked reductions in the magnitude of late decline of hypoxic ventilatory response occurred in mice heterozygous for a mutation in the PDGFR-β.…”

Neonatal maternal separation induces sex-specific augmentation of the hypercapnic ventilatory response in awake rat

“…sponse since it does not normally occur during hypercapnic challenge. Adenosine, cellular acidification, a change in the balance between excitatory (glutamate) and inhibitory (GABA) inputs, and activation of the platelet derived growth factor ␤-receptor at the level of the NTS are mechanisms that likely contribute to the frequency "roll-off" during hypoxia (11). Since this is the first time that an experimental treatment appears to elicit f depression during a hypercapnic challenge, it is difficult to explain why, unlike all other groups, NMS males did not maintain a constant f throughout the hypercapnic period.…”