Hypertension Induced by Vascular Endothelial Growth Factor Signaling Pathway Inhibition: Mechanisms and Potential Use as a Biomarker
Section snippets
Hypertension with VEGF Inhibition
As VEGF-targeted therapies entered the clinic, it became clear that hypertension and proteinuria were major toxicities of this drug class—both the biologics and the small molecules. Proteinuria as a consequence of VEGF inhibition is discussed by Eremina and Quaggin in an accompanying article in this issue of Seminars in Nephrology (see p. 582), therefore this article will focus on hypertension in patients treated with VEGF-targeted therapy. Hypertension occurs in up to 80% of patients on some
Mechanisms of VEGF-Associated Hypertension: Clues from Preeclampsia
Recent advances in our understanding of preeclampsia give reason to believe that hypertension in both patients with preeclampsia and patients taking anti-angiogenic therapy share a common pathogenesis. Preeclampsia is a disease of pregnancy affecting 5% to 7% of women in their second and third trimesters, and is marked by hypertension, proteinuria, and edema. This condition is characterized by systemic endothelial dysfunction, and, if left untreated, ascites, pulmonary edema, thrombocytopenia,
Inhibition of Endothelium-Derived Relaxing Factors
High-dose VEGF infusion into rabbits induces systemic vasodilation and causes an immediate decrease in blood pressure28 that can be inhibited by the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (Fig. 2).26 VEGF, acting through VEGFR-2, activates eNOS activity through AKT,26 leading to increased vasodilatory NO production (Fig. 3). Bevacizumab has been shown to decrease NO levels in vitro,29 and given that preeclampsia is characterized by deficient NO production, these observations
Capillary Rarefaction
Substantial evidence exists to show that chronic VEGF inhibition causes capillary rarefaction, both in preclinical models and in human beings. This capillary rarefaction may increase afterload and thereby contribute to the pathophysiology of hypertension induced by VEGF signaling pathway (VSP) inhibition. Chronic VEGF depletion causes reduced microvascular EC survival, ultimately leading to a net reduction in tissue microvessel density.35 The endothelial insult may additionally cause local
Alterations in the Pressure Natriuresis Relationship
Many decades of hypertension research have established the kidney's ability to excrete sodium in response to chronic increases in arterial pressure (the pressure-natriuresis relationship) as a critical regulatory response to increased blood pressure. For chronic hypertension to occur, a defect in renal sodium excretion has been seen in all forms of hypertension examined.38 At least two lines of evidence suggesting that VEGF inhibition might similarly shift the pressure-natriuresis curve as an
The Renin-Angiotensin Axis
Although endothelial dysfunction might be expected to cause glomerular ischemia with up-regulation of the renin-angiotensin-aldosterone axis, in fact no experimental evidence supports a role for this pathway. Facemire et al,30 using DC101, a VEGF-receptor inhibitor in mice, showed that renin messenger RNA (mRNA) and aldosterone urinary excretion were actually decreased when compared with control mice. In the only published study examining this in human beings, renin and aldosterone levels were
Other Vasoconstrictive Pathways
Emerging data support a possible role for increased vasoconstrictive endothelin-1 (ET-1) in the pathogenesis of hypertension induced by anti-VEGF therapy. First, there is evidence that ET-1 plays a role in hypertension induced by a rat model of preeclampsia. Alexander et al43 from the Granger group showed increased levels of preproendothelin mRNA in renal medulla during preeclampsia, and also showed marked attenuation of blood pressure by an endothelin type A–receptor antagonist. In a follow-up
Hypertension as a Biomarker of Tumor Response
In addition to the importance of understanding these side effects for purposes of clinical management, there is increasing evidence that an increase in blood pressure in patients on these medications may predict better tumor response.46 The rationale is that hypertension is a mechanism-dependent effect of VSP inhibition (ie, it reflects effective in vivo inhibition of the VEGF signaling pathway).47 This raises a natural question: are patients who do not develop hypertension on these drugs being
Management of Hypertension Induced by Anti-Angiogenic Therapy
Although an abundance of data exist for managing essential hypertension, very little data exist to guide treatment of hypertension induced by VSP-inhibitor blockade. Nevertheless, the condition is clinically important and several general recommendations can be made, based in part on a recent interdisciplinary working group convened to study this topic.55 First, patients should have controlled blood pressure before starting therapy because they may be expected to have exacerbation of
Conclusions
The use of anti-angiogenic therapies is growing rapidly and nephrologists increasingly will be called upon to manage the renal and vascular side effects of these drugs. Hypertension on VEGF-targeted therapies is common and causes significant morbidity but it can be managed effectively and also may be a biomarker for tumor responsiveness. Understanding the mechanisms of VEGF-inhibitor–induced hypertension will lead to rational treatment of this complication, and may illuminate our understanding
References (55)
- et al.
Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells
Biochem Biophys Res Commun
(1989) Development and differentiation of endothelium
Kidney Int Suppl
(1998)- et al.
Molecular mechanisms of VEGF-A action during tissue repair
J Investig Dermatol Symp Proc
(2006) - et al.
Autocrine VEGF signaling is required for vascular homeostasis
Cell
(2007) - et al.
Anticancer therapeutics: “addictive” targets, multi-targeted drugs, new drug combinations
Drug Resist Updat
(2005) - et al.
Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension
Am J Kidney Dis
(2007) - et al.
Pre-eclampsia
Lancet
(2005) Nitric oxide dysfunction in the pathophysiology of preeclampsia
Nitric Oxide
(2000)- et al.
Vascular endothelial growth factor (VEGF)-A165-induced prostacyclin synthesis requires the activation of VEGF receptor-1 and -2 heterodimer
J Biol Chem
(2005) - et al.
Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase
FEBS Lett
(1997)
Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts
Am J Pathol
Role of the kidney sodium and fluid secretion in hypertension
Longitudinal study of the renin-angiotensin-aldosterone system in hypertensive pregnant women: deviations related to the development of superimposed preeclampsia
Am J Obstet Gynecol
Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab
Ann Oncol
Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma
Ann Oncol
Blood pressure as a potential biomarker of the efficacy angiogenesis inhibitor
Ann Oncol
Arterial hypertension and clinical benefit of sunitinib, sorafenib and bevacizumab in first and second-line treatment of metastatic renal cell cancer
Ann Oncol
Tumor angiogenesis: therapeutic implications
N Engl J Med
Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid
Science
Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele
Nature
Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene
Nature
Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression
Development
The vascular endothelial growth factor/fms-like tyrosine kinase system in human ovary during the menstrual cycle and early pregnancy
J Clin Endocrinol Metab
Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover
Proc Natl Acad Sci U S A
VEGF gradients, receptor activation, and sprout guidance in resting and exercising skeletal muscle
J Appl Physiol
Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor inhibitor
Clin J Am Soc Nephrol
A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer
N Engl J Med
Cited by (0)
This work was supported by National Institutes of Health grants DK073628 and DK084316, and a pilot grant from Harvard Catalyst: National Institutes of Health grant UL1 RR 025758-02, with financial contributions from participating institutions (all to B.D.H.), and a grant from the National Kidney Foundation (E.S.R.). S.A.K. is listed as a co-inventor on multiple patents held by the Beth Israel Deaconess Medical Center for the diagnosis and therapy of preeclampsia. These patents have been nonexclusively licensed to multiple companies. S.A.K. is a consultant to Beckman Coulter, Johnson & Johnson, Roche, and Abbott Diagnostics, which are developing biomarkers for preeclampsia diagnosis/prediction.