SMAD3 contributes to lung vascular remodeling in pulmonary arterial hypertension via MRTF disinhibition
Bibliographic record
Abstract
Introduction Vascular remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of vascular cells. Loss of bone morphogenetic protein receptor 2 (BMPR‐II) signaling and increased signaling via transforming growth factor β (TGF‐β) and its downstream mediators SMAD2/3 has been proposed to drive lung vascular remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH. Objective We thus proposed that SMAD3 may be dysregulated in PAH, and that loss of SMAD3 may present a master switch in the disease process. Specifically we hypothesized that SMAD3 loss may promote lung vascular remodeling via disinhibition of its interaction partner myocardin‐related transcription factor (MRTF) which drives muscle protein expression. Methods and Results SMAD3 was downregulated in lungs of PAH patients, and in pulmonary arteries of three PAH animal models (monocrotaline or sugen/hypoxia rats, and BMPR2 +/R899X mice with dysfunctional BMPR‐II). TGF‐β treatment replicated the loss of SMAD3 in pulmonary artery smooth muscle (huPASMCs) and endothelial (huPAECs) cells. SMAD3 silencing increased proliferation and migration in huPASMCs and huPAECs. Co‐immunoprecipitation revealed reduced interaction of MRTF with SMAD3 in TGF‐β treated huPASMCs and pulmonary arteries of PAH animal models. In huPASMC, loss of SMAD3 or BMPR‐II increased smooth muscle actin expression, which was attenuated by MRTF inhibition. Conversely, SMAD3 overexpression prevented actin stress fiber formation in BMPR2 silenced huPASMC. MRTF inhibition attenuated PAH and lung vascular remodeling in sugen/hypoxia rats. Conclusion Loss of SMAD3 presents a novel central pathomechanism in PAH that promotes both vascular cell proliferation and ‐ via MRTF disinhibition ‐ hypertrophy of huPASMC, thereby reconciling the parallel induction of a synthetic and contractile huPASMC phenotype. While basal MRTF signaling has been shown to maintain BMP‐regulated vascular homeostasis in healthy lungs, disinhibition of MRTF following functional loss of BMPR‐II and subsequent downregulation of SMAD3 drives lung vascular remodeling in PAH. Support or Funding Information This work was supported by the Erwin‐Schroedinger Fellowship of the Austrian FWF Foundation to DZ, and grants‐in‐aid from the Canadian Institutes of Health Research (CIHR) and the Heart & Stroke Foundation of Canada (HSFC) to WMK
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".