Differential regulation of angiogenesis in the developing mouse brain in response to exogenous activation of the hypoxia-inducible transcription factor system

Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer’s Disease Associates with Upregulated Angiopoietin and Downregulated Hypoxia-Inducible Factor

“…Several studies have reported a possible correlation between AD and ANG-TIE signaling, but its exact role remains unclear [67]. Our present finding that the Angpt1/Tie2 system is transcriptionally upregulated in Tg-ArcSwe mice might reflect dysregulation of vascular repair and vessel maturation, as also suggested in several studies demonstrating that ANGPT-2 inhibits the protective role of the ANGPT-1/TIE-2-system [19,[68][69][70].…”

“…Angiogenesis is a complex process involving both hypoxia-inducible factor (HIF)-dependent angiogenetic factors (e.g., vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor; VEGFR-1, angiopoietins (ANGPT-1 and ANGPT-2), and the endothelial tyrosine kinase receptor, TIE-2 and the VE GF co-receptor neuropilin; NRP-1) and HIF-independent angiogenetic factors (e.g., vascular endothelial growth factor receptor (VEGFR-2)). These factors are crucial in controlling and timing regenerative angiogenesis in the adult rodent brain [17][18][19]. Ubiquitously expressed hypoxia-inducible factor-1, alpha subunit (HIF-1␣) is involved in the cellular adaptation to low oxygen tension and has evoked interest for its potential neuroprotective role [16].…”

Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice

“…Specific pharmacological therapies to prevent cerebral lesions and developmental disorders in at-risk preterm and term infants at risk are not available. However, experimental studies have provided evidence of the protective effects of exogenous neurotrophic growth factors such as insulin-like growth factor 1 (IGF-1), recombinant human growth hormone (rhGH), and recombinant human erythropoietin (rhEPO) in the treatment of HI brain injury during the perinatal period [ 2 , 3 , 4 , 5 , 6 ]. These novel therapies target the complex cytotoxic cascade of cerebral hypoxic injury during the acute and subacute HI period that involves oxidative stress responses, glutamate-induced excitotoxicity, pro-inflammatory pathways, and neurovascular damage [ 7 , 8 ].…”

“…Erythropoietin (EPO) is a hematopoietic growth factor regulated by HIF-2 and an anti-inflammatory, anti-apoptotic, and pro-survival factor upon cerebral hypoxia [ 19 ] with neuroprotective potential in HI brain injury in neonatal rodents [ 4 , 5 , 20 ]. These protective effects are mediated via its binding to EPO receptor (EPOR) homodimers and Janus kinase 2 (Jak2) phosphorylation, multiple signaling pathways, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK-1/2), signal transducer and activator of transcription 5 (Stat5), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), and modification of the transcriptional activity of anti-apoptotic factors [ 19 , 20 ].…”

“…Beyond acute effects, rhEPO enhances longer-term regenerative cerebral processes such as angiogenesis via the PI3K/Akt signaling pathway [ 3 , 19 ] associated with upregulation of VEGF and ANGPTs and increased vessel density in the white matter, hippocampus, and parietal cortex [ 5 , 21 , 22 ]. Moreover, rhEPO increases cerebral protein levels of the TJ protein OCLN in neonatal rodent stroke [ 23 ], ventilation-induced cerebral white matter injury in preterm lambs [ 24 ], and traumatic brain injury [ 25 ], indicating its protective potential against hypoxia-induced BBB disruption.…”