Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis – implications for cardiovascular safety

Winnik, Stephan; Lohmann, Christine; Siciliani, Giovanni; Lukowicz, Tobias von; Kuschnerus, Kira; Kraenkel, Nicolle; Brokopp, Chad E.; Enseleit, Frank; Michels, Stephan; Ruschitzka, Frank; Lüscher, Thomas F.; Matter, Christian M.

doi:10.1016/j.ijcard.2013.03.010

Cited by 83 publications

(41 citation statements)

References 45 publications

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“…Experimental studies revealed that systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. The recommendation was, therefore, to determine cardiovascular safety profiles to improve patient selection for therapy and allow close monitoring of patients at increased cardiovascular risk 95. In human studies, Avery et al 96 found that the systemic exposure after the third monthly intravitreal injection was 13-fold greater for aflibercept and 70-fold greater for bevacizumab than for ranibizumab.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)

Schmidt‐Erfurth

Chong

Loewenstein³

et al. 2014

Br J Ophthalmol

483

423

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Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients.Trial registration numberNCT01318941.

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Section: Therapeutic Strategiesmentioning

confidence: 99%

Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)

Schmidt‐Erfurth

Chong

Loewenstein³

et al. 2014

Br J Ophthalmol

483

423

View full text Add to dashboard Cite

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“…Indeed, expression of signaling molecules in the VEGF pathway is elevated in several cardiovascular disorders including acute myocardial infarction, coronary artery disease and atherosclerosis (9)(10)(11). However, the exact mechanism(s) involved in the process by which VEGF modulates hepatoma cell proliferation and migration remain unclear.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-199a-5p inhibits VEGF-induced tumorigenesis through targeting oxidored-nitro domain-containing protein 1 in human HepG2 cells

et al. 2016

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Abstract. VEGF induces deterioration of hepatocellular carcinoma (HCC) by enhancing cell proliferation and migration. MicroRNAs regulate many cellular processes. In this study, we examined the regulation of tumorigenesis in HCC cells by microRNAs in relation to the effect of VEGF. Differences in microRNA expression between HepG2 and THLE-3 cells were characterized by microarray analysis. The results showed that miR-199a-5p expression was markedly downregulated in HepG2 cells and was inhibited in VEGFoverexpressing HepG2 cells in a dose-and time-dependent manner. This miRNA also inhibited cell proliferation and migration, as demonstrated by MTT and cell migration assays. Oxidored-nitro domain-containing protein 1 (NOR 1 ), a nitroreductase, was identified as a downstream target gene of miR-199a-5p, and upregulation of NOR 1 proved critical for the inhibition of VEGF-induced cell proliferation and migration in HepG2 cells by miR-199a-5p. These results indicate that miR-199a-5p is critical for regulating cell proliferation and migration by targeting and upregulating NOR 1 in human HepG2 cells.

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“…54 These dynamics are confirmed by experimental studies with a pan-VEGF receptor inhibitor. 48 On the other hand, bevacizumab reduced neovascularization and growth of established plaques similar to other anti-angiogenesis inhibitors in experimental models. 55 Thus, VEGF signaling pathways inhibitors may be unique in their capacity to alter vasoreactivity and the atherosclerotic disease process with potentially important differences between them.…”

Section: Typical and Atypical Chest Painmentioning

confidence: 89%

“…83 Moreover, in experimental studies VEGF inhibitor therapy did not predispose to a vulnerable phenotype. 4855 For this reason, only vascular disrupting agents may be potent enough to disintegrate the fragile plaque neovessels leading to plaque hemorrhage. 84 An additional predisposing factor to acute vascular events with VEGF inhibitors, however, might be their impact on platelet function.…”

Section: Acute Coronary Syndromes (Acs)mentioning

confidence: 99%

Vascular Toxicities of Cancer Therapies

et al. 2016

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Since the late 1990s, there has been a steady decline in cancer-related mortality, in part related to the introduction of so-called “targeted therapies”. Intended to interfere with a specific molecular pathway, these therapies have, paradoxically, led to a number of “off-target” effects. The latest examples are tyrosine kinase inhibitors targeting the Philadelphia Chromosome mutation product, which have been associated with progressive atherosclerosis and acute vascular events. Additionally, agents designed to interfere with the vascular growth factor signaling pathway have vascular side effects ranging from hypertension to arterial events and cardiomyocyte toxicity. Interestingly, the risk of cardiotoxicity with drugs such as trastuzumab is predicted by preexisting cardiovascular risk factors and disease, posing the question of a vascular component to the pathophysiology. The effect on the coronary circulation has been the leading explanation for cardiotoxicity of 5-Fluorouracil and may be the underlying the mechanism of presentation of apical ballooning syndrome with various chemotherapeutics. Classical chemotherapeutics such as cisplatin, often used in combination with bleomycin and vinca alkaloids, can lead to vascular events including acute coronary thrombosis, may be associated with an increased long-term cardiovascular risk. This review is intended to provide an update on the evolving spectrum of vascular toxicities with cancer therapeutics, particularly as it pertains to clinical practice as well as the conceptualization of cardiovascular diseases. Vascular toxicity with cancer therapy: the old and the new, an evolving avenue.

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Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis – implications for cardiovascular safety

Cited by 83 publications

References 45 publications

Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)

Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)

MicroRNA-199a-5p inhibits VEGF-induced tumorigenesis through targeting oxidored-nitro domain-containing protein 1 in human HepG2 cells

Vascular Toxicities of Cancer Therapies

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