Tissue origin of endothelial cells determines immune system modulation and regulation of HIF-1α-, TGF-β-, and VEGF signaling
Bibliographic record
Abstract
Tight junctions of vascular endothelial cells in the central nervous system form the blood-brain and inner blood-retinal barriers, the integrity of which are further influenced by neighboring cells such as pericytes, astrocytes/Müller glial processes, and immune cells. In addition, the retina is shielded from the fenestrated endothelium of the choriocapillaris by the epithelial barrier of the retinal pigment epithelium. Dysfunction of the blood retinal barriers and/or proliferation of retinal and choroidal endothelial cells are caused by late stages of diabetic retinopathy (DR) and neovascular age-related macular degeneration (nAMD), the main causes of blindness in western countries. To elucidate endothelial-derived pathomechanisms in DR and nAMD, we established immortalized mouse cell lines of retinal and choroidal endothelial cells and immortalized brain endothelial cells as CNS-derived controls. We then used immunofluorescence staining, state-of-the-art long-range RNA sequencing and monolayer permeability assays to compare the functional state of these cells depending on their tissue origin. We furthermore demonstrate that activation of the wingless-type MMTV integration site (Wnt)/β-catenin signaling pathway restored blood brain/retinal barrier properties in brain and retinal endothelial cells, but unexpectedly increased permeability of choroidal endothelial cells. Transcriptome profiling showed that depending on the tissue origin of endothelial cells, regulation of the immune system was altered and pathways such as hypoxia-inducible factor (HIF)-1/2α, transforming growth factor (TGF)-β, and vascular endothelial growth factor (VEGF) were differentially regulated, strongly indicating their contribution in the molecular pathogenesis of DR and nAMD. These findings significantly increase the understanding of the vascular biology of endothelial cells, highlighting the fact that depending on their tissue origin, their contribution to vascular pathologies varies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".