The Vascular Endothelial Growth Factor Inhibitors Ranibizumab and Aflibercept Markedly Increase Expression of Atherosclerosis-Associated Inflammatory Mediators on Vascular Endothelial Cells

Abstract

IntroductionRecent studies have suggested that the VEGF inhibitors, Ranibizumab and Aflibercept may be associated with an excess of cardiovascular events, potentially driven by increasing atheroma instability, leading to plaque rupture and clinical events. Inflammation plays a key role in the progression of atherosclerotic plaque and particularly conversion to an unstable phenotype. Here, we sought to assess the in vitro effects of these drugs on the expression of key inflammatory mediators on endothelial cells.MethodsHuman coronary artery endothelial cells were co-incubated for 16h with Ranibizumab (0.11nM) or Aflibercept (0.45nM), as determined by each drug’s peak serum concentration (Cmax). Expression at protein (ELISA) and gene (RT-PCR) level of inflammatory chemokines CCL2, CCL5 and CXC3L1 as well as gene expression for the cell adhesion molecules VCAM-1, ICAM-1 and the key NF-κb protein p65 was assessed. VEGF-A protein levels were also determined.ResultsBoth drugs significantly increased chemokine, cell adhesion molecule (CAM) and p65 expression, while decreasing VEGF-A protein secretion. At equivalent Cmax concentrations, Aflibercept was significantly more pro-inflammatory than Ranibizumab. Reduction of secreted VEGF-A levels significantly attenuated inflammatory effects of both drugs, whereas blockade of the VEGF-A receptor or silencing of VEGF-A gene synthesis alone had no effect, suggesting that binding of drug to secreted VEGF-A is crucial in promoting inflammation. Finally, blockade of Toll-like receptor 4 significantly reduced inflammatory effects of both drugs.ConclusionWe demonstrated here, for the first time, that both drugs have potent pro-inflammatory effects, mediated via activation of Toll-like receptor 4 on the endothelial cell surface by drug bound to VEGF-A. Further studies are required to investigate whether these effects are also seen in vivo.

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

“…Of note, blocking of VEGF-A in keratinocyte-derived supernatants by Sunitinib or Bevacizumab treatment did not alter membrane expression of ICAM-1. These data are in line with previous findings demonstrating that VEGF-A inhibitors do not down-regulate ICAM-1, but could even induce ICAM-1 up-regulation [45]. Induction of ICAM-1 expression by VEGF-A inhibition is an emerging aspect that supports the association of immunotherapy and anti-angiogenic therapy in cancer treatment.…”

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

“…Of note, blocking of VEGF-A in keratinocyte-derived supernatants by Sunitinib treatment results into up-regulation of membrane ICAM-1. Similar results have been previously obtained with different VEGF-A inhibitors [38]. Induction of ICAM-1 expression by VEGF-A inhibition is an emerging aspect that supports the association of immunotherapy and anti-angiogenic therapy in cancer treatment.…”

Two-Week Aflibercept or Erlotinib Administration Does Not Induce Changes in Intestinal Morphology in Male Sprague–Dawley Rats But Aflibercept Affects Serum and Urine Metabolic Profiles

“…Although aflibercept does not appear to overtly induce apoptosis in cell models [35], [36], [37], [38], the metabolic shifts observed in our study could reflect aflibercept-mediated in vivo tissue hypoxia and oxidative stress that drive apoptotic processes. In addition, aflibercept has also been shown to enhance the generation of reactive oxygen species during oxidative stress [39] as well as promote the expression of inflammatory mediators in vascular endothelial cells [40]. Clinically, these findings suggest that aflibercept might exacerbate the oxidative stress of chemotherapy which contributes to the increased incidence of adverse effects observed during cancer treatment with antiangiogenic agents.…”