Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation

Mourad, Jean‐Jacques; Guetz, G. Des; Debbabi, Haythem; Lévy, Bernard

doi:10.1093/annonc/mdm550

Cited by 264 publications

(167 citation statements)

References 43 publications

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“…Hypertension has been commonly reported in all clinical trials testing inhibitors of angiogenesis with an incidence ranging from 11% to 43% in all studies. 26,27 The mechanism of elevated blood pressure in patients treated with antiangiogenic agents is not fully understood but probably involves endothelial dysfunction and capillary rarefaction. 26 Taken together, our findings have therapeutic implications for treatment strategies in hypertension and modulation of miRNA activity using antagomirs (miRNA inhibitor), or lipidbased nanoparticle delivery of miRNAs seems efficient.…”

Section: Discussionmentioning

confidence: 99%

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

et al. 2013

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Microvascular rarefaction increases vascular resistance and pressure in systemic arteries and is a hallmark of fixed essential hypertension. Preventing rarefaction by activation of angiogenic processes could lower blood pressure. Endothelial tip cells in angiogenic sprouts direct branching of microvascular networks; the process is regulated by microRNAs, particularly the miR-30 family. We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e). Loss-of-function experiments showed that only miR-30a reduced growth of intersegmental arterioles involving impaired tip cell function. Overexpression of miR-30a stimulated tip cell behavior resulting in augmented branching of intersegmental arterioles. In vitro and in vivo reporter assays showed that miR-30a directly targets the Notch ligand Dll4, a key inhibitor of tip cell formation. Coadministration of a Dll4 targeting morpholino in miR-30a morphants rescued the branching defects. Conversely, conditional overexpression of Notch intracellular domain restored arteriolar branching in miR-30a gain-of-function embryos. In human endothelial cells, loss of miR-30a increased DLL4 protein levels, activated Notch signaling as indicated in Notch reporter assays, and augmented Notch downstream effector, HEY2 and EFNB2 (ephrin-B2), expression. In spheroid assays, miR-30a loss- and gain-of-function affected tip cell behavior, consistent with miR-30a targeting Dll4. Our data suggest that miR-30a stimulates arteriolar branching by downregulating endothelial Dll4 expression, thereby controlling endothelial tip cell behavior. These findings could have relevance to the rarefaction process and, therefore, to hypertension.

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Section: Discussionmentioning

confidence: 99%

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

et al. 2013

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“…VEGF inhibition is likely to cause endothelial apoptosis, contributing to rarefaction. Two small studies showed rarefaction in patients treated with telatanib (BAY 57-9352) and bevacizumab [37,38], indicating that this may be a significant contributor to hypertension in patients treated with VEGFIs. Lastly, increased arterial stiffness within the proximal and distal blood vessels may also contribute to the pathogenesis of hypertension [39].…”

Section: Pathogenesismentioning

confidence: 99%

Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

et al. 2011

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Summary. The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time. Vascular endothelial growth factor inhibitors are associated with a broad range of adverse effects, with vascular toxicity being particularly serious. This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism), their incidence and severity, the current clinical management, and implications in the advanced cancer setting. Movement of these agents into the early disease setting will alter the impact of these toxicities.Search Strategy and Selection Criteria. Information for this review was collected by searching PubMed/ Medline and American Society of Clinical Oncology abstract databases. The medical subject heading terms used included toxicity, hypertension, thromboembolism, hemorrhage, intestinal perforation, risk factors, pharmacokinetics, and metabolism, combined with free text search terms including, but not limited to, VEGF inhibitor*, bevacizumab, sunitinib, and sorafenib. Articles published in English before March 2010 were included, in addition to information from case reports and pharmaceutical agent package inserts. The Oncologist 2011;16:432-444

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“…This new hypothesis is strengthened by recent studies highlighting that appearance of hypertension in patients with metastatic renal cell carcinoma receiving antiangiogenic treatment. 41,42 Finally, activation of vasculogenesis after antihypertensive drugs therapy may participate to the reduction in major macrovascular and microvascular events observed in patients with stroke or type 2 diabetes. 43,44 Sources of Funding …”

Section: Perspectivesmentioning

confidence: 99%

Hypertension Impairs Postnatal Vasculogenesis

et al. 2008

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Key Words: hypertension Ⅲ angiogenesis Ⅲ progenitor cells Ⅲ angiotensin converting enzyme Ⅲ angiotensin type I receptor T he revascularization process, including vasculogenesis, angiogenesis, and collateral growth, characterizes tissue repair and remodeling occurring in acute and chronic ischemic vascular diseases. In particular, postnatal vasculogenesis referred to the homing and differentiation of circulating progenitor cells from bone marrow or non-bone marrow origins 1 into endothelial cells within sites of active neovascularization. In addition, circulating progenitor cells may deliver angiogenic growth factors to pathological tissues and contribute to neovascularization and tissue/vessel remodeling by paracrine effects. 2,3 In most clinical settings, however, these natural adaptive responses to a compromised perfusion are insufficient to block the progression of ischemic diseases. Hence, certain cardiovascular risk factors including diabetes, aging, and hypercholesterolemia adversely affect postnatal vasculogenesis and revascularization in animals models of limb ischemia. 4 -7 In support of this view, patients with type I and II diabetes displayed a reduction in endothelial progenitor cell (EPC) number and angiogenicity. 8,9 In most forms of clinical and experimental hypertension, increased arterial blood pressure is associated with microvascular rarefaction and increased peripheral vascular resistances. 10 Similarly, postischemic reparative neovascularization is impaired in spontaneously hypertensive rats (SHR) as a function of progression of the hypertensive disease. 11,12 Several molecular and cellular mechanisms may be involved in the hypertension-induced impairment in vessel growth. First, the angiogenic capacity of serum derived from SHR was less than that from normotensive animals in a chick embryo chorio-allantoic membrane model. 13 Protein levels of key proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor are also reduced in hypertensive animals. 11,14 Second, previous obser-

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Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation

Cited by 264 publications

References 43 publications

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

Hypertension Impairs Postnatal Vasculogenesis

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