Antiangiogenesis targeting VEGF, irrespective of its underlying mechanism, is associated with a rise in ET-1. This rise is most likely a consequence of activation of ECs and not a direct consequence of VEGF deprivation. Preclinical studies with endothelin receptor blockers have clearly shown that activation of the ET-axis plays a pathogenic role in the rise in BP as well the proteinuria associated with antiangiogenic treatment (Figure 2). Because adverse effects may be a reason to discontinue antiangiogenic treatment, thereby limiting their therapeutic potential, studies exploring the usefulness of an endothelin receptor blocker in patients with cancer treated with these agents are warranted, especially so because ET-1 may exert proangiogenic effects and stimulates VEGF production.34
Finally, it may be proposed that the magnitude of the ET-1 rise during antiangiogenic treatment may be useful biomarker of the efficacy of treatment, unless loss of the ETB clearance receptor occurs during anti-angiogenic treatment as has been reported in experimental PE.35 Although the rise in BP or the development of hypertension has also been suggested as an efficacy parameter, the level of BP is the result of a large number of stimulatory and counteracting factors, limiting its value as suitable biomarker.
Figure 2. role of et-1 in the development of hypertension and proteinuria during antiangiogenesis.
note contributing role of VegF inhibition in development of kidney injury.
introduction part 2
42
reFerences
1. Ferrara N. Vascular endothelial growth factor: Basic science and clinical progress.
Endocr Rev. 2004;25:581-611.
2. Wu P, Nielsen TE, Clausen MH. Fda-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015;36:422-439.
3. Kappers MH, van Esch JH, Sluiter W, Sleijfer S, Danser AH, van den Meiracker AH.
Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels. Hypertension. 2010;56:675-681.
4. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sflt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649-658.
5. Ellis LM, Hicklin DJ. Vegf-targeted therapy: Mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579-591.
6. Takahashi S. Vascular endothelial growth factor (vegf), vegf receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull. 2011;34:1785-1788.
7. Facemire CS, Nixon AB, Griffiths R, Hurwitz H, Coffman TM. Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression. Hypertension. 2009;54:652-658.
8. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single vegf allele. Nature. 1996;380:435-439.
9. Kamba T, Tam BY, Hashizume H, et al. Vegf-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;
290:H560-576.
10. Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, Ferrara N, Nagy A, Roos KP, Iruela-Arispe ML. Autocrine vegf signaling is required for vascular homeostasis.
Cell. 2007;130:691-703.
11. Lankhorst S, Kappers MH, van Esch JH, Danser AH, van den Meiracker AH.
Hypertension during vascular endothelial growth factor inhibition: Focus on nitric oxide, endothelin-1, and oxidative stress. Antioxid Redox Signal. 2014;20:135-145.
12. Kostourou V, Cartwright JE, Johnstone AP, Boult JK, Cullis ER, Whitley G, Robinson SP. The role of tumour-derived inos in tumour progression and angiogenesis. Br J Cancer. 2011;104:83-90.
13. Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med. 1971;285:
1182-1186.
14. Escalante CP, Zalpour A. Vascular endothelial growth factor inhibitor-induced hypertension: Basics for primary care providers. Cardiol Res Pract. 2011;2011:816897.
15. Maitland ML, Kasza KE, Karrison T, Moshier K, Sit L, Black HR, Undevia SD, Stadler WM, Elliott WJ, Ratain MJ. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Cancer Res. 2009;15:6250-6257.
16. Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, Figlin RA, Baum MS,
chapter 2
43 Motzer RJ. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103:763-773.
17. Lankhorst S, Kappers MH, van Esch JH, Danser AH, van den Meiracker AH.
Mechanism of hypertension and proteinuria during angiogenesis inhibition: Evolving role of endothelin-1. J Hypertens. 2013;31:444-454.
18. Eremina V, Jefferson JA, Kowalewska J, et al. Vegf inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008; 358:1129-1136.
19. Lankhorst S, Baelde HJ, Kappers MH, Smedts FM, Hansen A, Clahsen-van Groningen MC, Sleijfer S, Mathijssen RH, Danser AH, van den Meiracker AH. Greater sensitivity of blood pressure than renal toxicity to tyrosine kinase receptor inhibition with sunitinib. Hypertension. 2015;66:543-549.
20. Wagner OF, Christ G, Wojta J, Vierhapper H, Parzer S, Nowotny PJ, Schneider B, Waldhausl W, Binder BR. Polar secretion of endothelin-1 by cultured endothelial cells.
J Biol Chem. 1992;267:16066-16068.
21. Bouallegue A, Daou GB, Srivastava AK. Endothelin-1-induced signaling pathways in vascular smooth muscle cells. Curr Vasc Pharmacol. 2007;5:45-52.
22. Ambs S, Merriam WG, Ogunfusika MO, Bennett WP, Ishibe N, Hussain SP, Tzeng EE, Geller DA, Billiar TR, Harris CC. P53 and vascular endothelial growth factor regulate tumor growth of nos2-expressing human carcinoma cells. Nat Med. 1998;4: 1371-1376.
23. Fiore G, Florio P, Micheli L, Nencini C, Rossi M, Cerretani D, Ambrosini G, Giorgi G, Petraglia F. Endothelin-1 triggers placental oxidative stress pathways: Putative role in preeclampsia. J Clin Endocrinol Metab. 2005;90:4205-4210.
24. Kappers MH, Smedts FM, Horn T, van Esch JH, Sleijfer S, Leijten F, Wesseling S, Strevens H, Jan Danser AH, van den Meiracker AH. The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system. Hypertension. 2011;58:295-302.
25. Verdonk K, Saleh L, Lankhorst S, Smilde JE, van Ingen MM, Garrelds IM, Friesema EC, Russcher H, van den Meiracker AH, Visser W, Danser AH. Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression. Hypertension. 2015;
65:1316-1323.
26. Banfor PN, Franklin PA, Segreti JA, Widomski DL, Davidsen SK, Albert DH, Cox BF, Fryer RM, Gintant GA. Eta receptor blockade with atrasentan prevents hypertension with the multitargeted tyrosine kinase inhibitor abt-869 in telemetry-instrumented rats.
J Cardiovasc Pharmacol. 2009;53:173-178.
27. Lankhorst S, Kappers MH, van Esch JH, Smedts FM, Sleijfer S, Mathijssen RH, Baelde HJ, Danser AH, van den Meiracker AH. Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib: Preclinical study. Hypertension.
2014;64:1282-1289.
28. Kappers MH, de Beer VJ, Zhou Z, Danser AH, Sleijfer S, Duncker DJ, van den Meiracker AH, Merkus D. Sunitinib-induced systemic vasoconstriction in swine is endothelin mediated and does not involve nitric oxide or oxidative stress. Hypertension.
introduction part 2
44
2012;59:151-157.
29. Saleh MA, Pollock JS, Pollock DM. Distinct actions of endothelin a-selective versus combined endothelin a/b receptor antagonists in early diabetic kidney disease. J Pharmacol Exp Ther. 2011;338:263-270.
30. Buelli S, Rosano L, Gagliardini E, et al. Beta-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury. J Am Soc Nephrol. 2014; 25: 523-533.
31. Matsuura A, Yamochi W, Hirata K, Kawashima S, Yokoyama M. Stimulatory interaction between vascular endothelial growth factor and endothelin-1 on each gene expression.
Hypertension. 1998;32:89-95.
32. Boulanger C, Luscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest. 1990;85:587-590.
33. Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, Smithies O, Takahashi N. Enos deficiency acts through endothelin to aggravate sflt-1-induced pre-eclampsia-like phenotype. J Am Soc Nephrol. 2012;23:652-660.
34. Salani D, Taraboletti G, Rosano L, Di Castro V, Borsotti P, Giavazzi R, Bagnato A.
Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am J Pathol. 2000;157:1703-1711.
35. George EM, Palei AC, Granger JP. Endothelin as a final common pathway in the pathophysiology of preeclampsia: Therapeutic implications. Curr Opin Nephrol Hypertens. 2012;21:157-162.
chapter 2
45
introduction part 2