Original Article
 

The Association between Vascular Endothelial Growth Factor-related Factors with Severity of Multiple Sclerosis

Abstract

Previous studies have demonstrated that vascular endothelial growth factor (VEGF) can trigger angiogenesis as well as inflammation through binding to its membranous receptor-1 on endothelial and inflammatory cells. We aimed to correlate the circulatory number of cells expressing such receptor as well as the serum level of VEGF and the soluble form of its receptor-1 (sVEGFR1) to the severity of multiple sclerosis (MS). This case-control study was done on 102 cases of MS lacking any other inflammatory or pathologic conditions and 75 healthy volunteer subjects. The severity of MS was examined by expanded disability status scale (EDSS). The serum levels of VEGF and sVEGFR1 were measured by ELISA, and the circulatory frequency of VEGFR1 expressing cells was counted by flowcytometry. Then, the correlation of these variables was evaluated by pearson’s correlation coefficient and spearman’s test. We also investigated the influence of sex, age, treatment duration, and the number of recurrences on such association through linear multivariate regression method. We found an increase in circulatory level of VEGFR1 expressing cells and the serum level of VEGF as well as sVEGFR1 in MS patients compared to healthy controls (p<0.001). The greater severity of MS, the higher VEGFR1 expressing cells (ρ=0.47; p<0.001), serum level of VEGF (ρ=0.44; p<0.001), and sVEGFR1 (ρ=0.76; p<0.001). Having adjusted the effects of VEGF on sVEGFR1, we found a significant association between the EDSS score and sVEGFR1 (β=0.007; p<0.001). Our findings revealed that circulatory membranous as well as soluble expression of VEGFR1 increases during angiogenic and inflammatory phenomena of MS. Such increase may exacerbate the symptoms and cause more disability.

Adams RD, Victor M, Ropper A. Multiple sclerosis and allied demyelinative diseases. Principles of Neurology New York: McGraw-Hill 1997; 902-27.
2. Carvalho JlF, Blank M, Shoenfeld Y. Vascular endothelial growth factor (VEGF) in autoimmune diseases. J Clin Immunol 2007; 27(3):246-56.
3. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 1996; 87(8):3336-43.
4. Poser CM. The role of trauma in the pathogenesis of multiple sclerosis: a review. Clin Neurol Neurosurg 1994;96(2):103-10.
5. Gay D, Esiri M. Bloo brain barrier damage in acute multiple sclerosis plaques. An immunocytological study. Brain 1991; 114(1):557-72.
6. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995; 146(5):1029-39.
7. Conn G, Soderman DD, Schaeffer M-T, Wile M, Hatcher VB, Thomas KA. Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci U S A 1990; 87(4):1323-7.
8. Claudio L, Kress Y, Norton WT, Brosnan C. Increased vesicular transport and decreased mitochondrial content in blood-brain barrier endothelial cells during experimental autoimmune encephalomyelitis. Am J Pathol 1989; 135(6):1157-68.
9. Su JJ, Osoegawa M, Matsuoka T, Minohara M, Tanaka M, Ishizu T, et al. Upregulation of vascular growth factors in multiple sclerosis: correlation with MRI findings. J Neurol Sci 2006; 243(1-2):21-30.
10. Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci U S A 2009; 106(6):1977-82.
11. Schlessinger J, Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron 1992; 9(3):383-91.
12. Kendall RL, Wang G, Thomas KA. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun 1996; 226(2):324-
8.
13. Sawano A, Takahashi T, Yamaguchi S, Aonuma M, Shibuya M. Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. Cell Growth Differ 1996; 7(2):213-21.
14. De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 1992;255(5047):989-91.
15. Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 1992; 187(3):1579-86.
16. Cao R, Xue Y, Hedlund E-M, Zhong Z, Tritsaris K, Tondelli B, et al. VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy. Proc Natl Acad Sci U S A 2010; 107(2):856-61.
17. Schwartz JD, Rowinsky EK, Youssoufian H, Pytowski B, Wu Y. Vascular endothelial growth factor receptor-1 in human cancer. Cancer 2010; 116(4 Suppl):1027-32.
18. Proescholdt MA, Jacobson S, Tresser N, Oldfield EH, Merrill MJ. Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats. J Neuropathol Exp Neurol 2002;61(10):914-25.
19. Graumann U, Reynolds R, Steck AJ, Schaeren-Wiemers N. Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol 2003;13(4):554-73.
20. Williams K, Ulvestad E, Hickey W. Immunology of multiple sclerosis. Clin Neurosci 1993; 2(3-4):229-45.
21. Tham E, Gielen A, Khademi M, Martin C, Piehl F.Decreased Expression of VEGF-A in Rat Experimental Autoimmune Encephalomyelitis and in Cerebrospinal Fluid Mononuclear Cells from Patients with Multiple Sclerosis. Scand J Immunol 2006; 64(6):609-22.
22. Kirk S, Karlik S. VEGF and vascular changes in chronic neuroinflammation. J Autoimmun 2003; 21(4):353-63.
23. Roscoe W, Welsh M, Carter D, Karlik S. VEGF and angiogenesis in acute and chronic MOG (35-55) peptide induced EAE. J Neuroimmunol 2009; 209(1-2):6-15.
24. Ferrara N, Gerber H-P, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9(6):669-76.
25. Goldman CK, Kendall RL, Cabrera G, Soroceanu L, Heike Y, Gillespie GY, et al. Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate. Proc Natl Acad Sci U S A 1998; 95(15):8795-800.
26. Waschbisch A, Manzel A, Linker RA, Lee D-H. Vascular pathology in multiple sclerosis: mind boosting or myth busting? Exp Transl Stroke Med 2011; 3(1):7.
27. Jackson JR, Seed M, Kircher C, Willoughby D, Winkler J. The codependence of angiogenesis and chronic inflammation. FASEB J 1997;11(6):457-65.
28. Schweighofer B, Testori J, Sturtzel C, Sattler S, Mayer H, Wagner O, et al. The VEGF-induced transcriptional response comprises gene clusters at the crossroad of angiogenesis and inflammation. Thromb Haemost 2009;
102(3):544-54.
29. Fukushima K, Miyamoto S, Tsukimori K, Kobayashi H, Seki H, Takeda S, et al. Tumor necrosis factor and vascular endothelial growth factor induce endothelial integrin repertories, regulating endovascular differentiation and apoptosis in a human extravillous trophoblast cell line. Biol Reprod 2005; 73(1):172-9.
30. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1(1):27-30.
31. Firestein GS. Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum 1996; 39(11):1781-90.
32. Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 1994; 152(8):4149-56.
33. Ballara S, Taylor PC, Reusch P, Marm' D, Feldmann M, Maini RN, et al. Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. Arthritis Rheum 2001;
44(9):2055-64.
34. De Bandt M, Grossin M, Weber AJ, Chopin M, Elbim C, Pla M, et al. Suppression of arthritis and protection from bone d-estruction by treatment with TNP-470/AGM-1470 in a transgenic mouse model of rheumatoid arthritis. Arthritis Rheum 2000; 43(9):2056-63.
35. Hitchon C, Wong K, Ma G, Reed J, Lyttle D, El- Gabalawy H. Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum 2002; 46(10):2587-97.
36. Miotla J, Maciewicz R, Kendrew J, Feldmann M, Paleolog E. Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Lab Invest 2000; 80(8):1195-205.
37. Takayama K, Ueno H, Nakanishi Y, Sakamoto T, Inoue K, Shimizu K, et al. Suppression of tumor angiogenesis and growth by gene transfer of a soluble form of vascular endothelial growth factor receptor into a remote organ. Cancer Res 2000; 60(8):2169-77.
38. Honda M, Sakamoto T, Ishibashi T, Inomata H, Ueno H.Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF/flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degeneration. Gene therapy 2000; 7(11):978-85.
39. Zhu C-S, Hu X-Q, Xiong Z-J, Lu Z-Q, Zhou G-Y, Wang D-J. Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) inhibits experimental autoimmune encephalomyelitis in dark Agouti (DA) rats. Life Sci 2008; 83(11-12):404-12.
40. Halin C, Fahrngruber H, Meingassner JG, Bold G, Littlewood-Evans A, Stuetz A, et al. Inhibition of chronic and acute skin inflammation by treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Am J Pathol 2008; 173(1):265-77.
41. Schonthaler HB, Huggenberger R, Wculek SK, Detmar M, Wagner EF. Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis. Proc Natl Acad Sci U S A 2009; 106(50):21264-9.
42. Seabrook TJ, Littlewood-Evans A, Brinkmann V, Pollinger B, Schnell C, Hiestand PC. Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions. J Neuroinflammation 2010;7(1):95.
43. Girolamo F, Coppola C, Ribatti D, Trojano M.Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol Commun 2014; 2:84.
44. Zhu C, Xiong Z, Chen X, Lu Z, Zhou G, Wang D, et al.Soluble vascular endothelial growth factor (VEGF) receptor-1 inhibits migration of human monocytic THP-1 cells in response to VEGF. Inflamm Res 2011; 60(8):769-74.

Files
IssueVol 15, No 3 (2016) QRcode
SectionOriginal Article(s)
Keywords
Multiple sclerosis Soluble VEGFR1 Vascular endothelial growth factor receptor 1

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Kouchaki E, Otroshi Shahreza B, Faraji S, Nikoueinejad H, Sehat M. The Association between Vascular Endothelial Growth Factor-related Factors with Severity of Multiple Sclerosis. Iran J Allergy Asthma Immunol. 2016;15(3):204-211.