Preliminary Analysis of the Mesenteric Vascular Phenotype of the Slc29a4‐Null Mouse
Bibliographic record
Abstract
SLC29A4 is a member of the equilibrative nucleoside transporter gene family. However, unlike the other SLC29 family members, the protein encoded by SLC29A4 (ENT4) is selective for the purine nucleoside adenosine, and then only under acidic conditions. Under normal physiological conditions (neutral pH), ENT4 functions as a polyspecific organic cation transporter, and was characterized previously as the plasma membrane monoamine transporter (PMAT). Both adenosine and monoamines such as serotonin have well established effects on the cardiovasculature, and adenosine in particular is known to be cardioprotective in response to ischemia‐reperfusion insult. Thus we hypothesized that the activity of ENT4/PMAT in the vasculature would contribute to the regulation of the vascular effects of serotonin and, under ischemic conditions, adenosine, making ENT4/PMAT a potential drug target for therapies aimed at reducing ischemia‐reperfusion injury. To begin to address this hypothesis we examined the vascular reactivity of mesenteric arteries isolated from both wild‐type mice and Slc29a4‐null mice under physiological conditions. Preliminary studies of mesenteric arteries isolated from male Slc29a4‐null mice showed significant functional differences as compared to arteries from male wild‐type mice. There was a complete loss of myogenic responsiveness in third order mesenteric arteries from Slc29a4‐null mice mounted in a pressure myograph and subjected to pressure steps from 20 to 120 mmHg. In the same vessels, passive dilations observed in response to pressure steps applied in calcium‐free conditions were unaltered, and external vessel diameters were not different from arteries from wild‐type mice indicating no increase in vessel stiffness or outward remodelling. In first order mesenteric arteries mounted under isometric conditions in a wire myograph, increases in tone elicited by the contractile agonists serotonin and phenylephrine were not significantly different between arteries from Slc29a4‐null and wild‐type mice in terms of both amplitude and sensitivity. However, under the same conditions, endothelium‐dependent relaxations to acetylcholine were significantly depressed in arteries from Slc29a4‐null mice compared to those from wild‐type mice. Furthermore, there was a shift in the contribution of the two main endothelium‐dependent vasorelaxants pathways, nitric oxide (NO) and endothelium‐dependent hyperpolarization (EDH), to acetylcholine‐evoked responses. In arteries from Slc29a4‐null mice there appeared to be a reduced contribution of EDH, manifested as a lack of effect of inhibitors of endothelial calcium‐activated potassium channels, and an increased reliance upon NO, manifested as a significant increase in the inhibitory effect of the NO synthase blocker L‐N G ‐nitro‐L‐arginine methylester on responses to acetylcholine. These data indicate that deletion of Slc29a4 may lead to loss of autoregulation and endothelial dysfunction which could have long term consequences for regulation of blood flow and pressure. Support or Funding Information This study is supported by a grant to JRH and FP from the Heart and Stroke Foundation of Canada (GIA G‐16‐00012740).
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 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".