Description
Excessive vascular permeability causes damaging tissue oedema in neovascular and inflammatory diseases and is, in part, driven by the vascular endothelial growth factor VEGF. Several molecular pathways have been implicated in VEGF-induced permeability signal transduction, including recruitment of a SRC family kinase by the VEGF-activated tyrosine kinase receptor VEGFR2 via the T-cell specific adaptor TSAd. To assess the expression of signal transducers in this pathway across organ vasculature in an unbiased manner, we examined bulk and single-cell RNAseq, proteomics and epigenomics EC data. All known signa transducers proposed to act in VEGF-induced permeability signal transduction could be detected, except TSAd, which was not detected or detected at extremely low levels, concordant with known models of leaky transcription. Extremely low or absent TSAd transcripts and/or protein were also found in datasets derived from VEGF-stimulated ECs and ECs of tumours with increased vascular leakiness. Epigenomics data indicated that the TSAd promoter was located in closed chromatin in normal and tumour ECs. Overall, our results suggest that TSAd is unlikely to be a critical signal transducer in VEGF-induced permeability signalling.
Lay Abstract
In patients with eye diseases such as diabetic retinopathy and age-related macular degeneration, or who have had a heart attack or stroke, excess fluid from the blood leaks across the vascular endothelial cell barrier and builds up in the affected organs, thereby exacerbating tissue damage. We have previously built a compendium of transcriptomic data from endothelial cell samples from five different mouse and human tissues and used it to study genes involved in vascular leakage. Unexpectedly, the SH2D2A gene, which encodes the TSAd protein that has been proposed as a target for therapies seeking to stem pathological vascular leakage, was absent or detected at extremely low levels in endothelial cells from all tissues included in the compendium. We found the same result when we examined datasets that examined protein levels in endothelial cells or had recorded DNA modifications that regulate gene activity. Even in cancer samples, in which vascular leakage is particularly abundant, TSAd remained absent or too low. Based on these findings, we recommend that researchers and pharmaceutical companies trying to stem vascular leakage should not focus their effort on targeting TSAd.
| Lay Title | Bioinformatics data challenge the proposed role for TSAd in vascular permeability |
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| Role | Postdoctoral Researcher |