{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:12:43Z","timestamp":1786983163640,"version":"build-2736575974"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,2,21]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">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\u2010ribose) 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\u2010regulated transient receptor potential cation channel, subfamily M, member 2 (TRPM2), a redox\u2010sensitive calcium channel, may be important. We investigated whether PARP\/TRPM2 plays a role in VEGFi\u2010induced vascular dysfunction and whether PARP inhibition ameliorates the vasculopathy associated with VEGF inhibition.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Human vascular smooth muscle cells (VSMCs), human aortic endothelial cells, and wild\u2010type mouse mesenteric arteries were studied. Cells\/arteries were exposed to axitinib (VEGFi) alone and in combination with olaparib. Reactive oxygen species production, Ca\n              <jats:sup>2+<\/jats:sup>\n              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\u2010dependent manner. Endothelial dysfunction and hypercontractile responses were ameliorated by olaparib and a TRPM2 blocker (8\u2010Br\u2010cADPR). VSMC reactive oxygen species production, Ca\n              <jats:sup>2+<\/jats:sup>\n              influx, and phosphorylation of myosin light chain 20 and endothelial nitric oxide synthase (Thr\n              <jats:sup>495<\/jats:sup>\n              ) were augmented by axitinib and attenuated by olaparib and TRPM2 inhibition. Proinflammatory markers were upregulated in axitinib\u2010stimulated VSMCs, which was reduced by reactive oxygen species scavengers and PARP\u2010TRPM2 inhibition. Human aortic endothelial cells exposed to combined olaparib and axitinib showed nitric oxide levels similar to VEGF\u2010stimulated cells.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Axitinib\u2010mediated 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\u2010treated patients with cancer.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.122.027769","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T12:29:49Z","timestamp":1676896189000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Role of PARP and TRPM2 in VEGF Inhibitor\u2010Induced Vascular Dysfunction"],"prefix":"10.1161","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5158-9263","authenticated-orcid":false,"given":"Karla B.","family":"Neves","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow United Kingdom"},{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rheure","family":"Alves\u2010Lopes","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augusto C.","family":"Montezano","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow United Kingdom"},{"name":"Research Institute of the McGill University Health Centre (RI\u2010MUHC) McGill University Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0670-0887","authenticated-orcid":false,"given":"Rhian M.","family":"Touyz","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow United Kingdom"},{"name":"Research Institute of the McGill University Health Centre 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