Intussusceptive angiogenesis-on-a-chip: Evidence for transluminal vascular bridging by endothelial delamination
Bibliographic record
Abstract
Abstract Intussusceptive angiogenesis is an increasingly recognized vessel duplication process that generates and reshapes microvascular beds. However, the mechanism by which a vessel splits into two is poorly understood. Particularly vexing is formation of the hallmark transluminal endothelial cell bridge. How an endothelial cell comes to cross a flowing lumen rather than line it is enigmatic. To elucidate this, we used a microvessel-on-a-chip strategy, creating a micro-conduit coherently lined with flow-sensitive endothelial cells but in which transluminal bridges also formed. Bridge morphologies ranged from filamentous strand to multicellular columns with a central core. These bridge architectures were found to recapitulate those in microvessels in embryos, tumours, diseased organs, and the dermis of patients with limb-threatening ischemia. Time-lapse, multi-plane, 3D microscopy of the micro-physiologic conduit revealed that bridges arose from endothelial cells oriented orthogonal to flow that partially released from the wall while retaining attachments at the ends. This delamination process was blocked by hyperactivation of Rho and augmented by interventions that weaken cell-substrate interactions, including inhibiting non-muscle myosin II and blocking α5ß1 integrin but, interestingly, not αvß3 integrin. Thus, endothelial cells can leave their monolayer and transect a flowing lumen through controlled delamination. This previously unrecognized lumen entry program could explain the launch of intussusceptive angiogenesis and opens a framework for intervening. Significance Statement Rapid generation of small blood vessels is vital for embryonic development and many diseases. An efficient means of creating a new microvessel is for an existing vessel to split into two, a process recognized for over 35 years. However, the cellular events underlying vessel splitting remain largely a mystery. The challenge is how to look inside a microvessel and capture transient events. We address this challenge using a microvessel-on-a-chip strategy. We discovered that select endothelial cells lining the wall can partially lift to transect the lumen. This resolves the paradox of an adhesion-dependent cell reaching across a pressurized lumen. It also reframes microvascular therapy considerations, including for diabetics with leg ulcers, a condition we show has hallmarks of microvessel splitting.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".