Developmental changes in HIF transcription factor in carotid body: relevance for O2 sensing by chemoreceptors.
Before birth, the peripheral chemoreceptors located in the carotid bodies (CB) are adapted to the low fetal Po(2) and are relatively insensitive to hypoxia. After birth, the sensitivity of the CB to hypoxia is reset in response to the rise in Po(2). The mechanism underlying this resetting, which requires several days to complete, remains unknown. We have investigated the possibility that the hypoxia-inducible factors HIF-1alpha and HIF-2alpha, which are activated by oxygen deprivation, are involved in this resetting process. Accordingly, we used immunostaining and densitometry to quantitate the levels of the HIF-1alpha and HIF-2alpha proteins in the rat CB during early perinatal life and after exposure to in vivo hypoxia during adolescence. Tyrosine hydroxylase (TH) was used as a marker for catecholaminergic neurons and oxygen-sensitive cells in the CB. Double-immunostaining revealed constitutive expression of HIF-1alpha in both glomus cells (TH+) and sustentacular cells (TH-) of the CB of adolescent rats. However, immunoreactivity toward HIF-2alpha was restricted to glomus cells. After exposure to hypoxia (8% O(2), 6 h), the expression of HIF-1alpha was selectively up-regulated in glomus cells and apparent translocation of both HIF-1alpha and HIF-2alpha to the nucleus was observed. Both of these proteins were expressed constitutively in the CB during the perinatal transition period. During the first postnatal week, the intensity of immunostaining for HIF-1alpha in glomus cells decreased markedly, whereas the level of HIF-2alpha remained constant. We suggest that this selective down-regulation of HIF-1alpha may be involved in the postnatal maturation of CB responsiveness to hypoxia.
Roux
Jean-Christophe
JC
Department of Woman and Child Health, Neonatal Research Unit, Karolinska Institutet, S-171 76 Stockholm, Sweden. Jean-Christophe.Roux@kbh.ki.se
Brismar
Hjalmar
H
Aperia
Anita
A
Lagercrantz
Hugo
H
D021581:Active Transport, Cell Nucleus; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002344:Carotid Body / Q000196:embryology / Q000378:metabolism*; D015687:Cell Hypoxia; D002628:Chemoreceptor Cells / Q000737:chemistry*; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014446:Tyrosine 3-Monooxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D015534:Trans-Activators; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1