Yasemen ADALI, Osman YILMAZ, Ali Necati GÖKMEN, Duygu GÜREL, Canan DEMİR, Şadiye Canan ÇOKER, Eyüp Sabri UÇAN, Meral KARAMAN

Effects of bevacizumab administration on the hypoxia - induced pulmonary hypertension rat model

Background/aim: Bevacizumab is a chemotherapeutic drug, which selectively binds to vascular endothelial growth factor (VEGF) and mainly inhibits angiogenesis and neovascularization. We aimed to study the possible effects of bevacizumab on right ventricular pressure (RVP), right ventricular hypertrophy, and VEGF, in hypoxia - induced pulmonary hypertension (PH) rat model. Materials and methods: 24 adult Wistar Albino rats were randomly divided into four groups: control group - saline; Bevacizumab Group; PH Group; PH + Bevacizumab Group. In hypoxia - induced model, 10% oxygen and 90% nitrogen were applied in a plexiglas box for eight days to PH Group and PH + Bevacizumab Group. On day eight, RVPs were measured directly from the heart, and then animals were sacrificed. Heart and lung tissues were examined, and Fulton index was measured. Results: RVP, Fulton index, and tissue VEGF scores were significantly lower in PH + Bevacizumab group than PH group: median (ranges), RVP, mmHg, 37.8 (33.0–39.0) and 32.3 (28.0–35.0), p: 0.01; Fulton index: 0.30 (0.29–0.33) and 0.25 (0.24–0.26), p: 0.003; tissue VEGF scores: 5.1 (4.8–5.3) and 4.0 (3.8 4.1), p: 0.004, respectively. Conclusion: Bevacizumab, which is indeed an antineoplastic agent, might have a favorable effect on hypoxia - induced pulmonary hypertension.Key words: Hypertension, pulmonary, bevacizumab, hypoxia

PDF

___

1. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European Respiratory Journal 2015; 46 (4): 903-975. doi: 10.1183/13993003.01032-2015
2. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D et al. Definitions and diagnosis of pulmonary hypertension. Journal of the American College of Cardiology 2013; 62 (25 Suppl): D42-D50. doi: 10.1016/j.jacc.2013.10.032
3. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 2010; 121 (18): 2045-2066. doi: 10.1161/CIRCULATIONAHA.108.847707
4. Tuder R, Flook B, Voelkel N. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. Journal of Clinical Investigation 1995; 95 (4): 1798-1807. doi: 10.1172/JCI117858
5. Cool C, Stewart J, Werahera P, Miller G, Williams R et al. Threedimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. American Journal of Pathology 1999; 155 (2): 411-419. doi: 10.1016/S0002-9440(10)65137-1
6. Tuder R, Chacon M, Alger L, Wang J, Taraseviciene-Stewart L et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. Journal of Pathology 2001; 195 (3): 367-374. doi: 10.1002/path.953
7. Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon GW et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB Journal: official publication of the Federation of American Societies for Experimental Biology 2001; 15 (2): 427-438. doi: 10.1096/fj.00-0343com
8. Dumas J, Bardou M, Goirand F, Dumas M. Hypoxic pulmonary vasoconstriction. General Pharmacology 1999; 33 (4): 289- 297. doi: 10.1016/s0306-3623(99)00026-9 9. Moudgil R, Michelakis E, Archer SL. Hypoxic pulmonary vasoconstriction. Journal of Applied Physiology (1985) 2005; 98 (1): 390-403. doi: 10.1152/japplphysiol.00733.2004
10. Sweeney M, Yuan JX. Hypoxic pulmonary vasoconstriction: role of voltage-gated potassium channels. Respiratory Research 2000; 1 (1): 40-48. doi: 10.1186/rr11
11. Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. Journal of Molecular and Cellular Cardiology 2008; 44 (1): 14-30. doi: 10.1016/j. yjmcc.2007.09.006
12. Cohen MT, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin®) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 2007; 12 (6): 713-718. doi: 10.1634/theoncologist.12-6-713
13. Raatschen HJ, Simon GH, Fu Y, Sennino B, Shames DM et al. Vascular permeability during antiangiogenesis treatment: MR imaging assay results as biomarker for subsequent tumor growth in rats. Radiology 2008; 247 (2): 391-399. doi: 10.1148/ radiol.2472070363
14. Bäuerle T, Hilbig H, Bartling S, Kiessling F, Kersten A et al. Bevacizumab inhibits breast cancer-induced osteolysis, surrounding soft tissue metastasis, and angiogenesis in rats as visualized by VCT and MRI. Neoplasia 2008; 10 (5): 511-520. doi: 10.1593/neo.08220
15. Partovian C, Adnot S, Raffestin B, Louzier V, Levame M et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. American Journal of Respiratory Cell and Molecular Biology 2000; 23 (6): 762-771. doi: 10.1165/ ajrcmb.23.6.4106
16. Christou H, Yoshida A, Arthur V, Morita T, Kourembanas S. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. American Journal of Respiratory Cell and Molecular Biology 1998; 18 (6): 768-776. doi: 10.1165/ajrcmb.18.6.2980
17. Partovian C, Adnot S, Eddahibi S, Teiger E, Levame M et al. Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension. American Journal of Physiology 1998; 275 (6): H1948-H1956. doi: 10.1152/ajpheart.1998.275.6.H1948
18. Laudi S, Steudel W, Jonscher K, Schöning W, Schniedewind B et al. Comparison of lung proteome profiles in two rodent models of pulmonary arterial hypertension. Proteomics 2007; 7 (14): 2469-2478. doi: 10.1002/pmic.200600848
19. Adnot S, Raffestin B, Eddahibi S, Braquet P, Chabrier PE. Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. Journal of Clinical Investigation 1991; 87 (1): 155-162. doi: 10.1172/ JCI114965
20. Yuyama H, Fujimori A, Sanagi M, Koakutsu A, Noguchi Y et al. A novel and selective endotheline ETa receptor antagonist YM598 prevents the development of chronic hypoxia-induced pulmonary hypertension in rats. Vascular Pharmacology 2005; 43 (1): 40-46. doi: 10.1016/j.vph.2005.03.001
21. Oka M, Homma N, Taraseviciene-Stewart L, Morris KG, Kraskauskas D et al. Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circulation Research 2007; 100 (6): 923-929. doi: 10.1161/01.RES.0000261658.12024.18
22. Azoulay E, Eddahibi S, Marcos E, Levame M, Harf A et al. Granulocyte colony-stimulating factor enhances alphanaphthylthiourea-induced pulmonary hypertension. Journal of Applied Physiology (1985) 2003; 94 (5): 2027-2033. doi: 10.1152/ japplphysiol.00807.2002
23. Farkas L, Farkas D, Ask K, Möller A, Gauldie J et al. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. Journal of Clinical Investigation 2009; 119 (5): 1298-1311. doi: 10.1172/JCI36136
24 Rondelet B, Kerbaul F, Beneden RV, Motte S, Fesler P et al. Signaling molecules in overcirculation-induced pulmonary hypertension in piglets: effects of sildenafil therapy. Circulation 2004; 110 (15): 2220-2225. doi: 10.1161/01.CIR.0000143836.40431.F5
25. Reiner A, Neumeister B, Spona J, Reiner G, Schemper M et al. Immunocytochemical localization of estrogen and progesterone receptor and prognosis in human primary breast cancer. Cancer Research 1990; 50 (21): 7057-7061
26. Meinshausen N. Hierarchical Testing of Variable Importance. Biometrika 2008; 95 (2): 265-278. doi: 10.1093/biomet/asn007
27. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. American Journal of Physiology-Lung Cellular and Molecular Physiology 2009; 297 (6): L1013-L1032. doi: 10.1152/ajplung.00217.2009
28. Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 2007; 104 (4): 1342- 1347. doi: 10.1073/pnas.0605080104
29. Selimovic N, Bergh CH, Andersson B, Sakiniene E, Carlsten H et al. Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension. European Respiratory Journal 2009; 34 (3): 662-668. doi: 10.1183/09031936.00174908
30. Carman BL, Predescu DN, Machado R, Predescu SA. Plexiform Arteriopathy in Rodent Models of Pulmonary Arterial Hypertension. The American Journal of Pathology 2019; 189 (6): 1133-1144. doi: 10.1016/j.ajpath.2019.02.005
31. Grover RF. Pulmonary circulation in animals and man at high altitude. Annals of the New York Academy of Sciences 1965; 127 (1): 632-639. doi: 10.1111/j.1749-6632.1965.tb49429.x
32. He LS, Chang SW, Voelkel NF. Pulmonary vascular reactivity in Fischer rats. Journal of Applied Physiology (1985) 1991; 70 (4): 1861-1866. doi: 10.1152/jappl.1991.70.4.1861
33. Sato K, Webb S, Tucker A, Rabinovitch M, O’Brien RF et al. Factors influencing the idiopathic development of pulmonary hypertension in the fawn hooded rat. The American Review of Respiratory Disease 1992; 145 (4 Pt 1): 793-797. doi: 10.1164/ ajrccm/145.4_Pt_1.793
34. Mirrakhimov AE, Strohl KP. High-altitude pulmonary hypertension: an update on disease pathogenesis and management. The Open Cardiovascular Medicine Journal 2016; 10: 19-27. doi: 10.2174/1874192401610010019
35. Bigham AW, Lee FS. Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes & Development 2014; 28 (20): 2189-2204. doi: 10.1101/gad.250167.114
36. Lahm T, Crisostomo PR, Markel TA, Wang M, Lillemoe KD et al. The critical role of vascular endothelial growth factor in pulmonary vascular remodeling after lung injury. Shock 2007; 28 (1): 4-14. doi: 10.1097/shk.0b013e31804d1998
37. Papaioannou AI, Kostikas K, Kollia P, Gourgoulianis KI. Clinical implications for vascular endothelial growth factor in the lung: friend or foe? Respiratory Research 2006; 7 (1): 128. doi: 10.1186/1465-9921-7-128
38. Winter MP, Sharma S, Altmann J, Seidl V, Panzenböck A et al. Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension. Basic Research in Cardiology 2020; 115 (6): 58. doi: 10.1007/s00395-020-0811-5
39. Tille JC, Wood J, Mandriota SJ, Schnell C, Ferrari S et al. Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro. Journal of Pharmacology and Experimental Therapeutics 2001; 299 (3): 1073-1085
40. Koolwijk P, Peters E, van der Vecht B, Hornig C, Weich HA et al. Involvement of VEGFR-2 (kdr/fk-1) but not VEGFR-1 (ft-1) in VEGF-A and VEGF-C-induced tube formation by human microvascular endothelial cells in fibrin matrices in vitro. Angiogenesis 2001; 4 (1): 53-60. doi: 10.1023/a:1016637700638
41. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Research 1997; 57 (20): 4593-4599
42. De Falco S. Antiangiogenesis therapy: an update after the first decade. Korean Journal of Internal Medicine 2014; 29 (1): 1-11. doi: 10.3904/kjim.2014.29.1.1
43. Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. Journal of Clinical Oncology 2008; 26 (1): 76-82. doi: 10.1200/JCO.2007.12.1939
44. Liotta M, Rose PG, Escobar PF. Pulmonary hypertension in two patients treated with bevacizumab for recurrent ovarian cancer. Gynecologic Oncology 2009; 115 (2): 308-309. doi: 10.1016/j.ygyno.2009.08.003
45. Taugourdeau-Raymond S, Rouby F, Default A, Jean-Pastor MJ; French Network of Pharmacovigilance Centers. Bevacizumabinduced serious side-effects: a review of the French pharmacovigilance database. European Journal of Clinical Pharmacology 2012; 68 (7): 1103-1107. doi: 10.1007/s00228- 012-1232-7