Abstract 38: Cyclin-Dependent Kinase Inhibitor 2B Regulates Transforming Growth Factor Beta 1 Mediated Smooth Muscle Cell Recruitment to Ischemic Blood Vessels
Bibliographic record
Abstract
Peripheral artery disease (PAD) is a highly morbid condition affecting nearly 8.5 million Americans. Genome wide association studies (GWAS) have identified genetic variation at the chromosome 9p21 cardiovascular risk locus as an important source of heritable PAD risk. However, it is unknown whether this association is secondary to an increase in atherosclerosis or is the result of a separate angiogenesis-related mechanism. Quantitative ultrastructural evaluation of human plaque laden vascular samples revealed that carriers of the 9p21 risk allele displayed a significantly increased burden of immature intraplaque microvessels than carriers of the ancestral allele. To determine whether this process occurs under non-atherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking Cdkn2b; a candidate gene we previously identified to have reduced expression in human carriers of the 9p21 risk allele. These animals developed advanced hind-limb ischemia and digital auto-amputation, relative to wild-type controls. Interestingly, in situ and in vitro hypoxic assays identified this defect to be a consequence of pro-angiogenic behavior displayed by CDKN2B deficient endothelial cells (EC) and impaired smooth muscle cell (SMC) recruitment to the developing neovessel. Exploratory microarray studies performed to identify the mechanism involved, revealed that TGFβ1 signaling is significantly induced in cultured CDKN2B -deficient cells; a finding later confirmed in the vasculature of individuals carrying the 9p21 risk allele. Subsequent molecular signaling studies reveal this increase to be a result of impaired expression of the inhibitory factor, SMAD-7. Increased TGFβ1 signaling was ultimately found to manifest the upregulation of a poorly studied effector molecule, TGFβ1-induced-1, which is a TGFβ-‘rheostat’ known to have antagonistic effects on the EC and SMC. Dual knockdown and rescue studies confirmed the reversibility of the proposed mechanism, in vitro. Taken together these findings suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis, but may also impair TGFβ1 signaling and hypoxic neovessel maturation consequently resulting in PAD.
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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) | 0.004 | 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".