Neves, K. B. , Alves‐Lopes, R. , Montezano, A. C. and Touyz, R. M. (2023) Role of PARP and TRPM2 in VEGF inhibitor‐induced vascular dysfunction. Journal of the American Heart Association, 12(4), e027769. (doi: 10.1161/JAHA.122.027769) (PMID:36802924) (PMCID:PMC10111475)
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Abstract
Background: Hypertension and vascular toxicity are major unwanted side effects of antiangiogenic drugs, such as vascular endothelial growth factor inhibitors (VEGFis), which are effective anticancer drugs but have unwanted side effects, including vascular toxicity and hypertension. Poly (ADP‐ribose) polymerase (PARP) inhibitors, used to treat ovarian and other cancers, have also been associated with elevated blood pressure. However, when patients with cancer receive both olaparib, a PARP inhibitor, and VEGFi, the risk of blood pressure elevation is reduced. Underlying molecular mechanisms are unclear, but PARP‐regulated transient receptor potential cation channel, subfamily M, member 2 (TRPM2), a redox‐sensitive calcium channel, may be important. We investigated whether PARP/TRPM2 plays a role in VEGFi‐induced vascular dysfunction and whether PARP inhibition ameliorates the vasculopathy associated with VEGF inhibition. Methods and Results: Human vascular smooth muscle cells (VSMCs), human aortic endothelial cells, and wild‐type mouse mesenteric arteries were studied. Cells/arteries were exposed to axitinib (VEGFi) alone and in combination with olaparib. Reactive oxygen species production, Ca2+ influx, protein/gene analysis, PARP activity, and TRPM2 signaling were assessed in VSMCs, and nitric oxide levels were determined in endothelial cells. Vascular function was assessed by myography. Axitinib increased PARP activity in VSMCs in a reactive oxygen species‐dependent manner. Endothelial dysfunction and hypercontractile responses were ameliorated by olaparib and a TRPM2 blocker (8‐Br‐cADPR). VSMC reactive oxygen species production, Ca2+ influx, and phosphorylation of myosin light chain 20 and endothelial nitric oxide synthase (Thr495) were augmented by axitinib and attenuated by olaparib and TRPM2 inhibition. Proinflammatory markers were upregulated in axitinib‐stimulated VSMCs, which was reduced by reactive oxygen species scavengers and PARP‐TRPM2 inhibition. Human aortic endothelial cells exposed to combined olaparib and axitinib showed nitric oxide levels similar to VEGF‐stimulated cells. Conclusions: Axitinib‐mediated vascular dysfunction involves PARP and TRPM2, which, when inhibited, ameliorate the injurious effects of VEGFi. Our findings define a potential mechanism whereby PARP inhibitor may attenuate vascular toxicity in VEGFi‐treated patients with cancer.
| Item Type: | Articles |
|---|---|
| Additional Information: | This study was supported by grants from the British Heart Foundation (BHF; RE/13/5/30177; 18/6/34217; CH/12/29762). Dr Montezano was supported through a Walton Foundation fellowship, University of Glasgow. Dr Touyz is supported by grants from the Leducq Foundation, Dr. Phil Gold Chair, McGill University, and the European Commission. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Montezano, Dr Augusto and Alves Moreira Lopes, Dr Rheure and Touyz, Professor Rhian and Neves, Dr Karla |
| Authors: | Neves, K. B., Alves‐Lopes, R., Montezano, A. C., and Touyz, R. M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Journal of the American Heart Association |
| Publisher: | American Heart Association |
| ISSN: | 2047-9980 |
| ISSN (Online): | 2047-9980 |
| Published Online: | 20 February 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Journal of the American Heart Association 12(4): e027769 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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