Angiogenesis Dysregulation in Term Asphyxiated Newborns Treated with Hypothermia

Abstract

BackgroundNeonatal encephalopathy following birth asphyxia is a major predictor of long-term neurological impairment. Therapeutic hypothermia is currently the standard of care to prevent brain injury in asphyxiated newborns but is not protective in all cases. More robust and versatile treatment options are needed. Angiogenesis is a demonstrated therapeutic target in adult stroke. However, no systematic study examines the expression of angiogenesis-related markers following birth asphyxia in human newborns.ObjectiveThis study aimed to evaluate the expression of angiogenesis-related protein markers in asphyxiated newborns developing and not developing brain injury compared to healthy control newborns.Design/MethodsTwelve asphyxiated newborns treated with hypothermia were prospectively enrolled; six developed eventual brain injury and six did not. Four healthy control newborns were also included. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study the plasma concentration of 49 angiogenesis-related proteins. Mean protein concentrations were compared between each group of newborns.ResultsCompared to healthy newborns, asphyxiated newborns not developing brain injury showed up-regulation of pro-angiogenic proteins, including fatty acid binding protein-4, glucose-6-phosphate isomerase, neuropilin-1, and receptor tyrosine-protein kinase erbB-3; this up-regulation was not evident in asphyxiated newborns eventually developing brain injury. Also, asphyxiated newborns developing brain injury showed a decreased expression of anti-angiogenic proteins, including insulin-growth factor binding proteins -1, -4, and -6, compared to healthy newborns.ConclusionsThese findings suggest that angiogenesis pathways are dysregulated following birth asphyxia and are putatively involved in brain injury pathology and recovery.

Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy

“…This dysregulation was evidenced by the observation that asphyxiated newborns with brain injury had decreased expression of insulin-growth factor binding protein-1, -4, and -6, which are anti-angiogenic proteins. While asphyxiated newborns that did not develop brain injury showed increases in fatty acid binding protein 4, glucose-6-phosphate isomerase, expression of neuropilin-1 (a vascular endothelial growth factor receptor-2 co-receptor), and receptor tyrosine-protein kinase erbB-3, which are proteins associated with endothelial cell survival, proliferation, and migration [ 45 ]. Thus, angiogenesis seems to be a viable target in newborns with HIE [ 44 ].…”

Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury

“…Following HI brain injury in the adult human, a robust angiogenic response occurs within 3-4 days (178). However, several studies indicate that in the neonate, this response is limited and occurs much later, and ischemic tissue presents with severe and chronic signs of vascular degeneration spreading beyond the site of injury (179)(180)(181). Indeed, a small study has associated the presence of proangiogenic factors in the serum of asphyxiated neonates with better outcomes (181), and although MK does not appear to be critical for the development of the vascular system (11), MK does promote angiogenesis in certain situations.…”

“…However, several studies indicate that in the neonate, this response is limited and occurs much later, and ischemic tissue presents with severe and chronic signs of vascular degeneration spreading beyond the site of injury (179)(180)(181). Indeed, a small study has associated the presence of proangiogenic factors in the serum of asphyxiated neonates with better outcomes (181), and although MK does not appear to be critical for the development of the vascular system (11), MK does promote angiogenesis in certain situations. Angiogenesis is severely compromised in MK KO adult mice subjected to occlusion of the right femoral artery (hindlimb ischemia model) as assessed via immunohistochemistry using markers for proliferation (Ki67) and endothelial cells (CD31) (11).…”

Targeted temperature management: State of the Art

“…Hypothermia also increases the concentration of neurotrophins, including brain-derived neurotrophic factor (BDNF), as well as enhances angiogenesis in ischaemic areas, reducing also the effect of glutamate and other neurotransmitters, resulting from their excessive release in pathological states of the central nervous system [19][20][21][22]. In the hypothermia phase, apoptosis is also reduced, including modulation of MAP (mitogen-activated protein) kinases signal pathways, inhibition of TNF-α (tumour necrosis factor-α) and caspase-induced proapoptotic cellular signal pathways, which play an important role in the regulation of programmable cell death, as well as lowering the level and activity of apoptosis-initiating proteins: p53-activator protein of apoptosis genes, calpain, cathepsins, granzymes, apoptosis-inducing factor (AIF) and C-delta protein kinase, with simultaneous increase of antiapoptotic factors: C-epsilon protein kinase, Bcl-2 protein and serine-threonine kinase Act [23][24][25][26].…”