Remodelling of the endothelial extracellular matrix promotes smooth muscle cell hyperplasia in pulmonary hypertension due to left heart disease
Bibliographic record
Abstract
AIMS: Hyperplasia of pulmonary arterial smooth muscle cells (SMCs) contributes to the progression of pulmonary hypertension (PH), yet the underlying pathomechanism of this process in PH secondary to left heart disease (PH-LHD) is poorly understood. We aimed to investigate the role of the endothelial extracellular matrix (ECM), specifically the pulmonary arterial basement membrane (BM), in influencing SMC proliferation and phenotypic changes in PH-LHD. METHODS AND RESULTS: SMC hyperplasia and endothelial ECM remodelling were characterized histologically on human pulmonary arterial samples, and by mass spectrometry, and atomic force microscopy on decellularized ECM (dECM) produced in vitro by endothelial cells isolated from pulmonary arteries (PA) of LHD patients without pulmonary hypertension (LHD w/o PH), PH-LHD patients, or healthy-heart controls. Proliferation and migration rates of SMC cultured on endothelial dECM were assessed by Ki67 immunostaining and by wound-healing assay, respectively. The role of mechanosensitive YAP1 in SMC hyperplasia was addressed in human cells and in an aortic-banding rat model of PH-LHD by analysing YAP1 activation and the effect of YAP1 inhibition. PA of LHD w/o PH and PH-LHD patients showed extensive remodelling of the BM. This was confirmed in vitro as altered composition and stiffening of dECM generated by respective patient endothelial cells. ECM remodelling was associated with SMC accumulation in the pulmonary arterial intima in patient samples and promoted SMC migration and proliferation in vitro. Conversely, dECM generated by healthy human endothelial cells reduced the hypermigration and hyperproliferation of SMC from LHD w/o PH and PH-LHD patients. Remodelling of the endothelial ECM in LHD w/o PH and PH-LHD patients also activated YAP1 in SMC, inhibition of which reduced SMC migration and proliferation in vitro. These findings were reproduced in vivo in a rat model of PH-LHD induced by aortic-banding. CONCLUSION: Here, we report endothelial ECM remodelling as a key mechanism driving SMC hyperplasia in PH-LHD. Notably, endothelial ECM remodelling is evident in both patients with LHD w/o PH and those with PH-LHD, raising the possibility that it may reflect an early event in LHD-induced pulmonary vascular remodelling. This ECM remodelling is associated with YAP1 in adjacent SMC, promoting their migration and proliferation and contributing to SMC hyperplasia. Consequently, targeting ECM remodelling and YAP1 activation may offer promising therapeutic strategies for preventing of PA remodelling in PH-LHD.
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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".