S-45-3: PARP INHIBITION AMELIORATES VEGF INHIBITOR-ASSOCIATED VASCULAR DYSFUNCTION VIA TRPM2
Bibliographic record
Abstract
Hypertension is a common unwanted effect of VEGF inhibitors (VEGFi) commonly used as anti-angiogenic drugs in cancer patients. The combination of VEGFi with olaparib, a PARP inhibitor (PARPi), has been shown to reduce VEGFi-induced hypertension. However underlying molecular mechanisms are unknown. PARP plays major role in the activation of TRPM2, a redox-sensitive calcium channel, which is associated with hypertension-induced vascular dysfunction. Objective: to elucidate whether PARP/TRPM2 axis is involved in the protective mechanisms of the combination VEGFi/PARPi in vascular cells. Design and Methods: Human vascular smooth muscle cells (VSMC), aortic endothelial cells (HAEC), and mice mesenteric arteries were used. Cells/arteries were exposed to axitinib (VEGFi) alone and in combination with olaparib (PARPi). Wire myography assessed vascular function. Reactive oxygen species (ROS) production, Ca2+ influx, protein/gene analysis, PARP activity, and TRPM2 siRNA were assessed in VSMC, and nitric oxide (NO) levels in HAEC. Results: Axitinib increased ROS production in hVSMC (RUL: 0.8 ± 0.2 [Ct] vs. 1.1 ± 0.09 [Axi]), which was followed by an increase in PARP activity (a.u.: 0.09 ± 0.03 [Ct] vs. 0.14 ± 0.004 [Axi]). Axitinib reduced ACh-induced vasodilation (% relaxation: 70.5 [Ct] vs. 34.8 [Axi]), an effect blocked by olaparib. U46619- and ET-1-induced vasoconstriction (% KCl-U4: 101.2 [Ct] vs. 141.4 [Axi]; ET-1: 122.6 [Ct] vs. 152.5 [Axi]) were increased by axitinib, which not observed with the combination axitinib plus olaparib. TRPM2 channel blocker (8-Br-cADPR) attenuated the hypercontractile effects and endothelial dysfunction induced by axitinib in mesenteric arteries. PARP and TRPM2 blockage also overturned the increase in VSMC Ca2+ influx induced by axitinib (AUC: 17541 ± 4708 [Ct] vs. 22249 ± 1438 [Axi]). This was also confirmed by TRPM2 siRNA. Phosphorylation of MLC20 in VSMC (a.u.: 0.028 ± 0.02 [Ct] vs. 0.04 ± 0.01 [Axi]), and eNOS (Thr495) in HAEC (a.u.: 0.99 ± 0.35 [Ct] vs. 1.35 ± 0.10 [Axi]) were enhanced by axitinib and prevented by olaparib and TRPM2 siRNA. HAEC exposed to the combination olaparib and axitinib showed NO levels similar to VEGF-stimulated cells. Pro-inflammatory markers (IL-6, MCP-1 and IL-1B) were also upregulated in axitinib-stimulated VSMC (p < 0.01), which was reduced by ROS and PARP-TRPM2 inhibition. Conclusions: We identify that PARP inhibition, by reducing TRPM2 activation, attenuates the vascular deleterious effects of axitinib. Our study defines novel mechanisms whereby the combination VEGFi/PARPi may reduce vascular dysfunction in VEGFi-treated cancer patients.
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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) | 0.001 | 0.001 |
| 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".