Small GTPase Cdc42 and p130 Crk‐associated substrate (p130Cas) contribute to actin cytoskeleton dynamics in the myogenic response of rat cerebral arteries to intraluminal pressure
Bibliographic record
Abstract
The constriction and relaxation of cerebral resistance arteries/arterioles in response to changes in intraluminal pressure, referred to as the myogenic response, is a key physiological mechanism for the regulation of blood pressure and flow in the brain. Actin cytoskeleton dynamics in vascular smooth muscle cells involving increased actin polymerization contribute to myogenic tone development in response to pressure elevation, but our understanding of the cellular mechanisms involved is limited. Members of the Rho family of small GTPases including RhoA, Rac1 and Cdc42 are established regulators of actin cytoskeleton dynamics. RhoA‐Rho‐associated coiled‐coil kinase (ROCK)‐mediated signaling contributes to actin polymerization in the cerebral arterial myogenic response, but whether Rac1 and/or Cdc42 play a role is not known. Here, the contribution of Rac1 and Cdc42 to myogenic vasoconstriction of endothelium‐denuded posterior cerebral arteries of adult rats was assessed by pressure myography combined with ultra‐sensitive immunoblotting to quantify G‐actin content, and level of phosphorylation of myosin regulatory light chain (LC20), myosin phosphatase targeting subunit 1 (MYPT1), p130Cas, N‐WASP, Arp2, cofilin and HSP27 in the absence and presence of GTPase inhibition. Treatment of vessels with Rac1 inhibitor Ehop‐016 (2–4 μM) before or after pressurization from 10 to 80 mmHg had no effect, whereas inhibition of Cdc42 with ML‐141 (1–10 μM) suppressed myogenic tone development. Significantly, ML‐141 (10 μM) did not affect the increase in LC20 or MYPT1‐T855 phosphorylation in response to pressurization from 10 to 80 mmHg, but it completely blocked the 50% decline in G‐actin content. Pressurization increased the level of p130Cas (Y165, Y249, Y410), N‐WASP (Y256), Arp2 (T237/238), HSP27 (S82) and cofilin (S3) phosphorylation. ML‐141 blocked the increase in p130Cas, N‐WASP, Arp2 and HSP27, but not cofilin phosphorylation. In contrast, inhibition of ROCK activity with H1152 (0.3 μM), which is known to suppress MYPT1, LC20 and cofilin phosphorylation, had no effect on the level of p130Cas, N‐WASP or Arp2 phosphorylation. Pharmacological suppression of alpha5‐integrins‐, focal adhesion kinase‐, or Src kinase‐dependent signaling, that inhibit MYPT1 and LC20 phosphorylation, G‐actin reduction and myogenic tone development, also prevented the pressure‐dependent increase in p130Cas, N‐WASP, Arp2, HSP27 and cofilin phosphorylation. Taken together, these data suggest that the myogenic response of rat cerebral arteries involves Cdc42 signaling that stimulates actin cytoskeleton dynamics via a p130Cas‐, N‐WASP‐ and Arp2‐dependent mechanism. This pathway is distinct from RhoA‐ROCK signaling that increases crossbridge cycling via increased MYPT1 and LC20 phosphorylation, as well as actin dynamics via cofilin. Activation of both RhoA and Cdc42 signaling in response to pressure elevation is dependent on integrin, focal adhesion kinase and Src kinase activity. Support or Funding Information This work was funded by a research grant from the Canadian Institutes of Health Research MOP‐97988 (WCC).
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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) | 0.001 | 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".