PDE1C regulates the dynamics of actin‐based structures in migrating human arterial smooth muscle cells
Bibliographic record
Abstract
Phenotypic remodeling and an associated increased migration by human arterial smooth muscle cells (HASMCs) are features of neo‐intimal hyperplasia that promote occlusive vascular diseases, including post‐angioplasty restenosis. Although it is established that cyclic adenosine 3′, 5′‐monophosphate (cAMP)‐mediated signaling inhibits overall HASMC migration, how this ubiquitous signaling system impacts the individual “steps” required for directed cell migration, including the dynamics of lamellipodial projections at their leading edges, is currently poorly defined. Using a modification of the trans‐well assay, our study highlights a critical role for a specific cyclic nucleotide phosphodiesterase, Phosphodiesterase 1C (PDE1C), in modulating lamellipodial dynamics in migrating HASMCs. Formation of HASMC lamellipodial projections in response to exposure of these cells to a chemotactic gradient (0.5% FBS) was assessed by quantifying the accumulation of actin‐rich structures on the underside of filters with 3 μm pores in 4hrs. When compared to vehicle‐treated controls, selective pharmacological inhibition of PDE1C (compound 33 (C‐33), Dart Neuroscience LLC) increased accumulation of lamellipodial structures significantly. Similarly, RNAi‐mediated knockdown of PDE1C using several distinct siRNA markedly increased accumulation of lamellipodial structures when compared to those formed in control siRNA transfected cells. In contrast, agents that increase intracellular cAMP by activating HASMC adenylyl cyclases (ACs) (i.e. forskolin) reduced accumulation of these actin‐rich structures in HASMCs exposed to a gradient of FBS. Most interestingly, lamellipodial projection accumulation in response to PDE1C inhibition, or knockdown, was also markedly antagonized by addition of forskolin. These results are consistent with the novel idea that PDE1C is acting locally at the leading edge of HASMCs to promote accumulation of lamellipodial structures and that this hyper‐localized effect is lost when HASMC cAMP levels are increased globally, using forskolin. Consistent with this, we show that PDE1C can associate with an A‐kinase anchoring protein AKAP79 and the cAMP effector Protein Kinase A (PKA). Overall, since each PDE1C and AKAP79 is found at the leading edge of migrating HASMCs, we suggest that PDE1C acts locally, via a PKA/AKAP79‐based signalosome, to regulate lamellipodial projection formation in migrating HASMCs. Support or Funding Information Canadian Institutes for Health Research (CIHR)
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 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".