Abstract
Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (106 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO- levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy: our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated proinflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients.
| Original language | English |
|---|---|
| Pages (from-to) | 978-988 |
| Number of pages | 11 |
| Journal | Cardiovascular Research |
| Volume | 115 |
| Issue number | 5 |
| Early online date | 11 Feb 2019 |
| DOIs | |
| Publication status | Published - 15 Apr 2019 |
Funding
This study was supported by the British Heart Foundation (BHF) [RE/13/5/ 30177 to R.M.T., BHF Chair CH/12/429762], Glasgow Experimental Cancer Figure 7 Putative mechanisms involving ET-1 system whereby MPs released under VEGFi treatment causes endothelial cell dysfunction. VEGF/VEGFR inhibition causes an increase in ECMPs release which suggests an endothelial injury. In addition to carry ET-1, MPs induce endothelial cells damage by increasing ET-1 production, inflammation and ROS production through ETA and ETB activation but also by down-regulating eNOS/NO signalling. The dys-regulation of endothelial cell function induced by MPs may induce vascular tone alterations and endothelial dysfunction, and may explain, at least partially, molecular mechanisms underlying VEGFi-associated hypertension. Medicine Centre funded by Cancer Research UK and Chief Scientist’s Office Scotland [A25174 to T.R.J.E.] and Cancer Research UK Glasgow Clinical Trials Unit (C1348/A25355 to R.J.).
Keywords
- cancer
- endothelial cell
- hypertension
- microparticles
- VEGF
