Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF.Electronic supplementary materialThe online version of this article (doi:10.1007/s10456-011-9249-6) contains supplementary material, which is available to authorized users.

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BackgroundAutism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear.MethodsThe dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERβ overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks.ResultsWe show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERβ (estrogen receptor β) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERβ suppression is due to LNG-mediated altered methylation on the ERβ promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERβ in the amygdala completely restores LNG-induced ERβ suppression and autism-like behaviors in offspring, while ERβ knockdown mimics this effect, indicating that ERβ expression in the amygdala plays an important role in autism-like behavior development.ConclusionsWe conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0159-3) contains supplementary material, which is available to authorized users.

Background: MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs that regulate gene expression and function, but little is known about regulation of miRNAs in the kidneys under normal or pathologic conditions. Here, we sought to investigate the potential involvement of miRNAs in renal ischemia/reperfusion (I/R) injury and angiogenesis and to define some of the miRNAs possibly associated with renal angiogenesis. Methods and Results: Male Balb/c mice were subjected to a standard renal I/R. CD31 immunostaining indicated a significant increase of microvessels in the ischemic region. VEGF and VEGFR2 expression were increased in renal I/R at both the mRNA and protein levels which were detected by qRT-PCR and Western blot, respectively. More importantly, 76 microRNAs exhibited more than 2-fold changes using Agilent microRNA microarray, which contains downregulation of 40 miRNAs and upregulation of 36 miRNAs. Upregulation of miR-210 was confirmed by qRT-PCR with prominent changes at 4 and 24 h after reperfusion. Furthermore, overexpression of miR-210 in HUVEC-12 cells enhances VEGF and VEGFR2 expression and promotes angiogenesis on Matrigel in vitro. Conclusion: These findings suggest miR-210 may be involved in targeting the VEGF signaling pathway to regulate angiogenesis after renal I/R injury, which provides novel insights into the angiogenesis mechanism of renal I/R injury.