Temporal expression analysis of angiogenesis-related genes in brain development

Abstract

BackgroundThe current knowledge on molecular pathogenesis of cerebral vascular malformations (CVM), which are believed to arise during development, is very limited. To unravel the molecular mechanisms involved in CVMs, a detailed understanding of the brain vascular development at molecular level is crucial. In this study, we aimed to explore the temporal and comparative expression profile of angiogenesis-related genes in the establishment of brain vasculature.MethodsExpression of a total of 113 angiogenesis-related genes during murine brain development has been analyzed using low-density array systems designed for angiogenesis-related genes. Bai1 (brain specific angiogenesis inhibitor-1), a recently identified novel anti-angiogenic gene, has been selected for further characterization.ResultsWe found that 62 out of 113 analyzed genes have expression in brain development at varying levels. Nineteen of these were differentially expressed between embryonic and postnatal stages (>1.5 fold). Bai1 is strongly expressed on growing blood vessels of cerebral cortex and hippocampus, partially expressed in the lateral regions of striatum, but mostly absent on the thalamus.ConclusionBy showing the comparative expression analysis of angiogenesis-related genes throughout brain development, the data presented here will be a crucial addition to further functional studies on cerebrovascular research.

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

“…BAI1 is a member of the adhesion GPCR subfamily (11), initially identified in a screen for p53-regulated genes (12). BAI1 is highly expressed in the normal brain but is epigenetically silenced in glioblastoma (12)(13)(14)(15). BAI1 has been shown to exert potent antiangiogenic and antitumorigenic effects (16)(17)(18), and its loss or mutation in several cancers suggests that it is a tumor suppressor (19).…”

Cerebral microbleeds in a neonatal rat model

“…Fetuses were exposed in utero to the dual pro-angiogenic stimuli of IUI plus low-dose maternal LPS (IUI+mLPS) on E19. Brains were studied 12–24 hours later (on E20) to evaluate markers of angiogenesis, including mRNA for Vegf , cluster of differentiation 31 (Cd31) , Mmp2 , Mmp9 , tissue inhibitor of metalloproteinase (Timp) 1 and Timp2 , as well as protein for CD31 (PECAM-1), MMP2 and MMP9 [ 30 ]. Quantitative real-time PCR showed that all of these angiogenic markers were significantly altered in periventricular areas of fetuses exposed to the dual stimuli, compared to naïve controls ( Fig 1A ).…”

Control of cerebrovascular patterning by neural activity during postnatal development

“…Knowing that the endothelium represents the ultimate effector undergoing structural changes, future studies could focus on investigating the genes that are regulated within endothelial cells upon modulation of neural activity. This approach is timely, since technological advances in gene analysis allow for a better understanding of cerebrovascular cell transcriptome (Ozkan et al, 2012; Zhang et al, 2014). Such approaches could be used to investigate candidate genes and identify new molecular players of vascular plasticity.…”

“…Receptor neuropilin-1 ( Nrp1 ) and its co-receptor VEGFR2 ( Kdr ) have recently been associated to postnatal angiogenesis and vascular remodeling after ischemic challenge (Gelfand et al, 2014). Another interesting candidate is Bai1 (brain-specific angiogenesis inhibitor-1), a G-protein coupled receptor present in vessels of the mouse brain throughout development with higher expression at the tips of angiogenic sprouts (Ozkan et al, 2012). Interestingly, while endothelial-specific expression of Bai1 has to be confirmed, Bai1 appears predominantly expressed in dense microvascular networks of the cerebral cortex at P14 (Ozkan et al, 2012), which is an age when cerebrovascular growth and remodeling are very active (Lacoste et al, 2014).…”

“…Another interesting candidate is Bai1 (brain-specific angiogenesis inhibitor-1), a G-protein coupled receptor present in vessels of the mouse brain throughout development with higher expression at the tips of angiogenic sprouts (Ozkan et al, 2012). Interestingly, while endothelial-specific expression of Bai1 has to be confirmed, Bai1 appears predominantly expressed in dense microvascular networks of the cerebral cortex at P14 (Ozkan et al, 2012), which is an age when cerebrovascular growth and remodeling are very active (Lacoste et al, 2014). Future studies could investigate whether candidates or new endothelial genes are regulated by neural activity in vivo during postnatal development.…”