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

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.

[1]  D. Ribatti,et al.  Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis , 2014, Acta neuropathologica communications.

[2]  R. Linker,et al.  Vascular pathology in multiple sclerosis: mind boosting or myth busting? , 2011, Experimental & Translational Stroke Medicine.

[3]  Xiaohong Chen,et al.  Soluble vascular endothelial growth factor (VEGF) receptor-1 inhibits migration of human monocytic THP-1 cells in response to VEGF , 2011, Inflammation Research.

[4]  C. Schnell,et al.  Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions , 2010, Journal of Neuroinflammation.

[5]  Yan Wu,et al.  Vascular endothelial growth factor receptor‐1 in human cancer , 2010, Cancer.

[6]  Zhen-ping Zhu,et al.  VEGFR1–mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy , 2009, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Michael Detmar,et al.  Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis , 2009, Proceedings of the National Academy of Sciences.

[8]  O. Wagner,et al.  The VEGF-induced transcriptional response comprises gene clusters at the crossroad of angiogenesis and inflammation , 2009, Thrombosis and Haemostasis.

[9]  S. Karlik,et al.  VEGF and angiogenesis in acute and chronic MOG(35–55) peptide induced EAE , 2009, Journal of Neuroimmunology.

[10]  A. T. Argaw,et al.  VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown , 2009, Proceedings of the National Academy of Sciences.

[11]  Zhengqi Lu,et al.  Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) inhibits experimental autoimmune encephalomyelitis in dark Agouti (DA) rats. , 2008, Life sciences.

[12]  M. Detmar,et al.  Inhibition of chronic and acute skin inflammation by treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. , 2008, The American journal of pathology.

[13]  Y. Shoenfeld,et al.  Vascular Endothelial Growth Factor (VEGF) in Autoimmune Diseases , 2007, Journal of Clinical Immunology.

[14]  M. Khademi,et al.  Decreased Expression of VEGF‐A in Rat Experimental Autoimmune Encephalomyelitis and in Cerebrospinal Fluid Mononuclear Cells from Patients with Multiple Sclerosis , 2006, Scandinavian journal of immunology.

[15]  F. Mihara,et al.  Upregulation of vascular growth factors in multiple sclerosis: Correlation with MRI findings , 2006, Journal of the Neurological Sciences.

[16]  S. Karlik,et al.  VEGF and vascular changes in chronic neuroinflammation. , 2003, Journal of autoimmunity.

[17]  R. Reynolds,et al.  Molecular Changes in Normal Appearing White Matter in Multiple Sclerosis are Characteristic of Neuroprotective Mechanisms Against Hypoxic Insult , 2003, Brain pathology.

[18]  N. Ferrara,et al.  The biology of VEGF and its receptors , 2003, Nature Medicine.

[19]  E. Oldfield,et al.  Vascular Endothelial Growth Factor Is Expressed in Multiple Sclerosis Plaques and Can Induce Inflammatory Lesions in Experimental Allergic Encephalomyelitis Rats , 2002, Journal of neuropathology and experimental neurology.

[20]  C. Hitchon,et al.  Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. , 2002, Arthritis and rheumatism.

[21]  M. Feldmann,et al.  Raised serum vascular endothelial growth factor levels are associated with destructive change in inflammatory arthritis. , 2001, Arthritis and rheumatism.

[22]  M. Pla,et al.  Suppression of arthritis and protection from bone destruction by treatment with TNP-470/AGM-1470 in a transgenic mouse model of rheumatoid arthritis. , 2000, Arthritis and rheumatism.

[23]  R. Maciewicz,et al.  Treatment with Soluble VEGF Receptor Reduces Disease Severity in Murine Collagen-Induced Arthritis , 2000, Laboratory Investigation.

[24]  H. Ueno,et al.  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 , 2000, Gene Therapy.

[25]  K. Inoue,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. , 2000, Cancer research.

[26]  K.,et al.  Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. Willoughby,et al.  The codependence of angiogenesis and chronic inflammation , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[28]  G. Firestein.  Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? , 1996, Arthritis and rheumatism.

[29]  A. Mantovani,et al.  Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. , 1996, Blood.

[30]  M. Shibuya,et al.  Flt-1 but not KDR/Flk-1 tyrosine kinase is a receptor for placenta growth factor, which is related to vascular endothelial growth factor. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[31]  H. Dvorak,et al.  Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. , 1995, The American journal of pathology.

[32]  C. Poser.  The role of trauma in the pathogenesis of multiple sclerosis: a review , 1994, Clinical Neurology and Neurosurgery.

[33]  G. Haines,et al.  Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. , 1994, Journal of immunology.

[34]  D. Dimitrov,et al.  Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. , 1992, Biochemical and biophysical research communications.

[35]  A. Ullrich,et al.  Growth factor signaling by receptor tyrosine kinases , 1992, Neuron.

[36]  H Ueno,et al.  The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. , 1992, Science.

[37]  M. Esiri,et al.  Blood-brain barrier damage in acute multiple sclerosis plaques. An immunocytological study. , 1991, Brain : a journal of neurology.

[38]  G. Conn,et al.  Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[39]  C. Brosnan,et al.  Increased vesicular transport and decreased mitochondrial content in blood-brain barrier endothelial cells during experimental autoimmune encephalomyelitis. , 1989, The American journal of pathology.

[40]  S. Hamano,et al.  [Childhood multiple sclerosis and allied demyelinative diseases]. , 1999, No to hattatsu = Brain and development.

[41]  R. Kendall,et al.  Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. , 1996, Biochemical and biophysical research communications.

[42]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[43]  J. Mussini,et al.  [Immunology of multiple sclerosis]. , 1982, La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris.