Role of the NF-kB/parkin/vegfr-1 Pathway Associated with Hypoxic-ischemic Insult in Germinal Matrix Samples of Newborn Infants

Objective: Given the high proliferative activity of germinal matrix and its direct correlation with hypoxemia, it is necessary to investigate the possible molecular regulation pathways, to understand the existing clinical relationship between the hypoxic-ischemic insult and the biomarkers NF-kB, AKT-3, Parkin, TRK-C and VEGFR-1.

Methods: A hundred and eighteen germinal matrix samples of the central nervous system of patients who died in the first 28 days of life were submitted to histological and immunohistochemistry analysis to identify the tissue immunoexpression of those biomarkers related to asphyxia, prematurity, and death events within 24h.

Results: A significantly increased tissue immunoexpression of NF-kB, AKT-3 and Parkin was observed in the germinal matrix of preterm infants. In addition, significantly decreased tissue immunoexpression of VEGFR-1 and NF-kB was observed in patients who experienced asphyxia followed by death within 24 hours.

Conclusions: The results suggest a direct involvement between the hypoxic-ischemic insult and NF-kB and VEGFR-1 markers since a decreased immunoexpression of these biomarkers was observed in asphyxiated patients. Furthermore, it is suggested that there was not enough time for VEGFR-1 to be transcribed, translated and expressed on the surface of the plasma membrane. This temporality can be observed in the relationship between NF-kB expression and the survival time of individuals who died within 24 hours, suggesting that this factor is essential for the production of VEGFR-1 and, therefore, to carry out the necessary remodeling effect to neovascularize the affected region.

References

Morales P, Bustamante D, Espina-Marchant P, Neira-Pena T, Gutierrez-Hernandez M, Allende-Castro C . Pathophysiology of perinatal asphyxia: can we predict and improve individual outcomes?. EPMA J. 2012; 2(2):211-30. PMC: 3405380. DOI: 10.1007/s13167-011-0100-3. View

Minet E, Ernest I, Michel G, Roland I, Remacle J, Raes M . HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5'UTR. Biochem Biophys Res Commun. 1999; 261(2):534-40. DOI: 10.1006/bbrc.1999.0995. View

van Uden P, Kenneth N, Rocha S . Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J. 2008; 412(3):477-84. PMC: 2474706. DOI: 10.1042/BJ20080476. View

Raets M, Dudink J, Govaert P . Neonatal disorders of germinal matrix. J Matern Fetal Neonatal Med. 2013; 28 Suppl 1:2286-90. DOI: 10.3109/14767058.2013.796169. View

Higginbotham H, Yokota Y, Anton E . Strategies for analyzing neuronal progenitor development and neuronal migration in the developing cerebral cortex. Cereb Cortex. 2010; 21(7):1465-74. PMC: 3116733. DOI: 10.1093/cercor/bhq197. View

Hayden M, Ghosh S . Regulation of NF-κB by TNF family cytokines. Semin Immunol. 2014; 26(3):253-66. PMC: 4156877. DOI: 10.1016/j.smim.2014.05.004. View

Ballabh P, Braun A, Nedergaard M . Anatomic analysis of blood vessels in germinal matrix, cerebral cortex, and white matter in developing infants. Pediatr Res. 2004; 56(1):117-24. DOI: 10.1203/01.PDR.0000130472.30874.FF. View

Jiang B, Zheng J, Aoki M, Vogt P . Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc Natl Acad Sci U S A. 2000; 97(4):1749-53. PMC: 26507. DOI: 10.1073/pnas.040560897. View

Wenger R . Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J. 2002; 16(10):1151-62. DOI: 10.1096/fj.01-0944rev. View

10.

Mulero M, Huxford T, Ghosh G . NF-κB, IκB, and IKK: Integral Components of Immune System Signaling. Adv Exp Med Biol. 2019; 1172:207-226. DOI: 10.1007/978-981-13-9367-9_10. View

11.

Jossin Y . Neuronal migration and the role of reelin during early development of the cerebral cortex. Mol Neurobiol. 2005; 30(3):225-51. DOI: 10.1385/MN:30:3:225. View

12.

Supramaniam V, Vontell R, Srinivasan L, Wyatt-Ashmead J, Hagberg H, Rutherford M . Microglia activation in the extremely preterm human brain. Pediatr Res. 2013; 73(3):301-9. DOI: 10.1038/pr.2012.186. View

13.

Osaki M, Oshimura M, Ito H . PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004; 9(6):667-76. DOI: 10.1023/B:APPT.0000045801.15585.dd. View

14.

Ballabh P, de Vries L . White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies. Nat Rev Neurol. 2021; 17(4):199-214. PMC: 8880688. DOI: 10.1038/s41582-020-00447-8. View

15.

Wang Y, Shan B, Liang Y, Wei H, Yuan J . Parkin regulates NF-κB by mediating site-specific ubiquitination of RIPK1. Cell Death Dis. 2018; 9(7):732. PMC: 6023924. DOI: 10.1038/s41419-018-0770-z. View

16.

Chen E, Mazure N, Cooper J, Giaccia A . Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation. Cancer Res. 2001; 61(6):2429-33. View

17.

Veloso F, Kassar L, Oliveira M, de Lima T, Bueno N, Gurgel R . Analysis of neonatal mortality risk factors in Brazil: a systematic review and meta-analysis of observational studies. J Pediatr (Rio J). 2019; 95(5):519-530. DOI: 10.1016/j.jped.2018.12.014. View

18.

Kaur C, Hao A, Wu C, Ling E . Origin of microglia. Microsc Res Tech. 2001; 54(1):2-9. DOI: 10.1002/jemt.1114. View