Hypoxia modifies levels of the SARS-CoV-2 cell entry proteins, angiotensin-converting enzyme 2, and furin in fetal human brain endothelial cells
Notice bibliographique
Résumé
•hfBECs express ACE2, TMPRSS2, and furin proteins associated with SARS-CoV-2 cell entry.•ACE2, TMPRSS2, and furin are modified by hypoxia.•The hypoxia effects on SARS-CoV-2 cell entry proteins are gestational age and time of exposure dependent.•The developing BBB is potentially vulnerable to SARS-CoV-2 infection. BACKGROUNDIt is not known whether human fetal brain endothelial cells that form the blood-brain barrier express angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin, which are SARS-CoV-2 cell entry proteins. Moreover, it is unclear whether hypoxia, commonly observed during severe maternal COVID-19, can modify their level of expression. We hypothesized that human fetal brain endothelial cells isolated from early- and midpregnancy brain microvessels express angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin. Furthermore, we hypothesized that hypoxia modifies their expression levels in a gestational age– and time-of-exposure–dependent manner.OBJECTIVEThis study aimed to investigate whether early- and midpregnancy human fetal brain endothelial cells express angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin SARS-CoV-2–associated cell entry proteins and to determine the effects of hypoxia on angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin expression levels in human fetal brain endothelial cells.STUDY DESIGNThis was a prospective study where human fetal brain endothelial cells isolated from early-pregnancy (12.4±0.7 weeks of gestation) and midpregnancy (17.9±0.5 weeks of gestation) fetal brain microvessels (6 per group) were exposed to different oxygen tensions (20%, 5%, and 1% oxygen) for 6, 24, and 48 hours. Angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin messenger RNA and protein levels and localization were assessed using quantitative polymerase chain reaction, Western blot testing, and immunofluorescence.RESULTSAngiotensin-converting enzyme 2, transmembrane serine protease 2, and furin co-localize with the endothelial cell marker von Willebrand factor in human fetal brain endothelial cells isolated from early pregnancy and midpregnancy. In early pregnancy, TMPRSS2 messenger RNA expression was decreased by 5% oxygen compared with 20% oxygen after 6 hours of exposure (P<.05). In midpregnancy, 5% oxygen down-regulated ACE2 messenger RNA compared with 20% oxygen after 24 hours (P<.05). Furin messenger RNA expression was decreased under 5% and 1% oxygen compared with 20% oxygen (P<.05) after 24 hours. In midpregnancy, angiotensin-converting enzyme 2 protein levels were decreased under 5% and 1% oxygen (P<.001) after 24 hours. In contrast, furin protein levels were increased under 1% oxygen compared with 20% oxygen after 24 hours (P<.05). At 48 hours, 1% oxygen increased angiotensin-converting enzyme 2 protein levels compared with 20% oxygen (P<.01).CONCLUSIONHypoxia modifies the expression of selected SARS-CoV-2 cell entry proteins in human fetal brain endothelial cells in a gestational age– and time-of-exposure–dependent manner. As severe COVID-19 may lead to maternal hypoxia, an altered expression of these proteins in the developing human blood-brain barrier could potentially lead to altered SARS-CoV-2 brain invasion and neurologic sequelae in neonates born to pregnancies complicated by SARS-CoV-2 infection. It is not known whether human fetal brain endothelial cells that form the blood-brain barrier express angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin, which are SARS-CoV-2 cell entry proteins. Moreover, it is unclear whether hypoxia, commonly observed during severe maternal COVID-19, can modify their level of expression. We hypothesized that human fetal brain endothelial cells isolated from early- and midpregnancy brain microvessels express angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin. Furthermore, we hypothesized that hypoxia modifies their expression levels in a gestational age– and time-of-exposure–dependent manner. This study aimed to investigate whether early- and midpregnancy human fetal brain endothelial cells express angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin SARS-CoV-2–associated cell entry proteins and to determine the effects of hypoxia on angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin expression levels in human fetal brain endothelial cells. This was a prospective study where human fetal brain endothelial cells isolated from early-pregnancy (12.4±0.7 weeks of gestation) and midpregnancy (17.9±0.5 weeks of gestation) fetal brain microvessels (6 per group) were exposed to different oxygen tensions (20%, 5%, and 1% oxygen) for 6, 24, and 48 hours. Angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin messenger RNA and protein levels and localization were assessed using quantitative polymerase chain reaction, Western blot testing, and immunofluorescence. Angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin co-localize with the endothelial cell marker von Willebrand factor in human fetal brain endothelial cells isolated from early pregnancy and midpregnancy. In early pregnancy, TMPRSS2 messenger RNA expression was decreased by 5% oxygen compared with 20% oxygen after 6 hours of exposure (P<.05). In midpregnancy, 5% oxygen down-regulated ACE2 messenger RNA compared with 20% oxygen after 24 hours (P<.05). Furin messenger RNA expression was decreased under 5% and 1% oxygen compared with 20% oxygen (P<.05) after 24 hours. In midpregnancy, angiotensin-converting enzyme 2 protein levels were decreased under 5% and 1% oxygen (P<.001) after 24 hours. In contrast, furin protein levels were increased under 1% oxygen compared with 20% oxygen after 24 hours (P<.05). At 48 hours, 1% oxygen increased angiotensin-converting enzyme 2 protein levels compared with 20% oxygen (P<.01). Hypoxia modifies the expression of selected SARS-CoV-2 cell entry proteins in human fetal brain endothelial cells in a gestational age– and time-of-exposure–dependent manner. As severe COVID-19 may lead to maternal hypoxia, an altered expression of these proteins in the developing human blood-brain barrier could potentially lead to altered SARS-CoV-2 brain invasion and neurologic sequelae in neonates born to pregnancies complicated by SARS-CoV-2 infection.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,008 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,001 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».