The vascular endothelial growth factor trap aflibercept induces vascular dysfunction and hypertension via attenuation of eNOS/NO signaling in mice

Dong, Zhi-Chao; Wu, Ming‐Ming; Zhang, Yun-Long; Wang, Qiushi; Chen, Liang; Yan, Xiao; Zou, Lei-Xin; Chen, Chen; Han, Xiao; Zhang, Bo; Zhang, Zhiren

doi:10.1038/s41401-020-00569-1

Cited by 11 publications

(10 citation statements)

References 59 publications

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“…The constitutive expression of the CD31 antigen on endothelial cells defines the morphology of these cells ( 70 ). eNOS uncoupling and the resulting oxidative stress are major drivers of endothelial dysfunction and atherogenesis ( 71 , 72 ). During endothelial injury, however, a reduction in NO release may lead to vasoconstriction and arterial obliteration ( 70 , 73 ).…”

Section: Discussionmentioning

confidence: 99%

Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer

Wang

He²,

Li³

et al. 2022

Front. Cardiovasc. Med.

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Hypertension is one of the main adverse effects of antiangiogenic tumor drugs and thus limits their application. The mechanism of hypertension caused by tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors is mainly related to inhibition of the nitric oxide (NO) pathway and activation of the endothelin pathway, as well as vascular rarefaction and increased salt sensitivity; consequently, prevention and treatment differ for this type of hypertension compared with primary hypertension. Apatinib is a highly selective TKI approved in China for the treatment of advanced or metastatic gastric cancer. The RhoA/ROCK pathway is involved in the pathogenesis of hypertension and mediates smooth muscle contraction, eNOS inhibition, endothelial dysfunction and vascular remodeling. In this study, in vivo experiments were performed to explore whether the RhoA/ROCK signaling pathway is part of a possible mechanism of apatinib in the treatment of gastric cancer-induced hypertension and the impairment of vascular remodeling and left ventricular function. Y27632, a selective small inhibitor of both ROCK1 and ROCK2, was combined with apatinib, and its efficacy was evaluated, wherein it can reduce hypertension induced by apatinib treatment in gastric cancer mice and weaken the activation of the RhoA/ROCK pathway by apatinib and a high-salt diet (HSD). Furthermore, Y-27632 improved aortic remodeling, fibrosis, endothelial dysfunction, superior mesenteric artery endothelial injury, left ventricular dysfunction and cardiac fibrosis in mice by weakening the activation of the RhoA/ROCK pathway. The expression of RhoA/ROCK pathway-related proteins and relative mRNA levels in mice after apatinib intervention were analyzed by various methods, and blood pressure and cardiac function indexes were compared. Endothelial and cardiac function and collagen levels in the aorta were also measured to assess vascular and cardiac fibrosis and to provide a basis for the prevention and treatment of this type of hypertension.

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Section: Discussionmentioning

confidence: 99%

Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer

Wang

He²,

Li³

et al. 2022

Front. Cardiovasc. Med.

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“…82 Another study in C57BL/6 mice showed that administration of a single-dose aflibercept led to a rapid and dose-dependent elevation in systolic blood pressure associated with NOX (NADPH oxidase) 1/NOX4mediated reactive oxygen species accumulation, impaired AKT (protein kinase B) /eNOS/NO signaling and EDR, reduced intracellular levels of L-arginine, and decreased expression of CAT-1 (cationic amino acid transporter-1). 83 L-arginine supplement significantly inhibited aflibercept-induced hypertension once again highlighting the role of NO signaling VEGFiinduced hypertension and potential therapeutic utility of L-arginine in this setting. 83 Additional postulated mechanisms for TKI-induced hypertension relate to interruption of downstream intracellular VEGF signaling and include decreased renal NO bioavailability via downregulation of soluble guanylate cyclase activity, inhibition of intrarenal NOS activity, activation of the renin-angiotensin-aldosterone system, and decreased fractional sodium excretion.…”

Section: Mechanisms Of Vegfi-induced Hypertensionmentioning

confidence: 80%

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

et al. 2023

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Cardiovascular disease and cancer are 2 of the leading causes of death worldwide. Although improvements in outcomes have been noted for both disease entities, the success of cancer therapies has come at the cost of at times very impactful adverse events such as cardiovascular events. Hypertension has been noted as both, a side effect as well as a risk factor for the cardiotoxicity of cancer therapies. Some of these dynamics are in keeping with the role of hypertension as a cardiovascular risk factor not only for heart failure, but also for the development of coronary and cerebrovascular disease, and kidney disease and its association with a higher morbidity and mortality overall. Other aspects such as the molecular mechanisms underlying the amplification of acute and long-term cardiotoxicity risk of anthracyclines and increase in blood pressure with various cancer therapeutics remain to be elucidated. In this review, we cover the latest clinical data regarding the risk of hypertension across a spectrum of novel anticancer therapies as well as the underlying known or postulated pathophysiological mechanisms. Furthermore, we review the acute and long-term implications for the amplification of the development of cardiotoxicity with drugs not commonly associated with hypertension such as anthracyclines. An outline of management strategies, including pharmacological and lifestyle interventions as well as models of care aimed to facilitate early detection and more timely management of hypertension in patients with cancer and survivors concludes this review, which overall aims to improve both cardiovascular and cancer-specific outcomes.

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“…Although an increasing number of pathological factors have been associated with hypertension, the specific mechanism of its pathogenesis remains unclear. Results of previous studies have demonstrated that endothelial dysfunction is closely associated with the occurrence and development of hypertension (4,5). Endothelial dysfunction is considered to be one of the main causes of microvascular and macrovascular complications associated with hypertension (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…Results of previous studies have demonstrated that endothelial dysfunction is closely associated with the occurrence and development of hypertension (4,5). Endothelial dysfunction is considered to be one of the main causes of microvascular and macrovascular complications associated with hypertension (4,5). In addition, endothelial dysfunction has been reported to be a major factor underlying hypertension in the heart and kidneys, causing organ dysfunction (6).…”

Section: Introductionmentioning

confidence: 99%

Pitavastatin maintains MAPK7 expression and alleviates angiotensin II‑induced vascular endothelial cell inflammation and injury

Liu

2021

Exp Ther Med

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Statins have been reported to suppress vascular remodeling in rats with spontaneous hypertension. However, the possible effects of the statin pitavastatin on hypertension-induced endothelial inflammation and injury remain to be fully elucidated. The present study aimed to evaluate the effects of pitavastatin on HUVEC injury and inflammation. HUVECs were exposed to angiotensin (Ang) II with or without pitavastatin co-treatment, after which MAPK7 expression was detected via reverse transcription-quantitative PCR and western blotting. MAPK7 expression was additionally silenced in HUVECs via transfection with short hairpin RNA, followed by Ang II treatment with or without pitavastatin. Cell viability, inflammation, reactive oxygen species (ROS) production, nitric oxide (NO) production and cell apoptosis were then measured by using Cell Conting Kit-8, ELISA, commercial corresponding kits and TUNEL staining, respectively. Western blotting was also used to determine the protein expression of endothelial NO synthase and endothelin 1, and the proteins involved in apoptosis. Results of the present study demonstrated that the expression levels of MAPK7 in Ang II-induced endothelial cells were decreased, which was reversed following treatment with pitavastatin. Pitavastatin reversed the Ang II-induced reduction in cell viability and reversed the Ang II-induced increase in inflammatory factor and ROS levels and apoptosis in HUVECs by activating MAPK7. Treatment with pitavastatin also increased the production of NO in addition to increasing the expression of endothelial NO synthase and endothelin-1 in Ang II-induced HUVECs through MAPK7 activation. Collectively, results from the present study demonstrated that treatment with pitavastatin preserves MAPK7 expression to alleviate Ang II-induced vascular endothelial cell inflammation and injury. Therefore, findings of the present study may help to elucidate the mechanisms underlying the effects of pitavastatin on vascular endothelial cell inflammation and injury.

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The vascular endothelial growth factor trap aflibercept induces vascular dysfunction and hypertension via attenuation of eNOS/NO signaling in mice

Cited by 11 publications

References 59 publications

Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer

Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

Pitavastatin maintains MAPK7 expression and alleviates angiotensin II‑induced vascular endothelial cell inflammation and injury

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