Serum Concentration of VEGF and PDGF-AA in Patients with Active Thyroid Orbitopathy before and after Immunosuppressive Therapy

M. Nowak; B. Marek; J. Karpe; B. Kos-Kudla; L. Sieminska; D. Kajdaniuk; M. Treszer

doi:10.1055/s-0034-1383579

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2014; 122(10): 582-586
DOI: 10.1055/s-0034-1383579

Article

Serum Concentration of VEGF and PDGF-AA in Patients with Active Thyroid Orbitopathy before and after Immunosuppressive Therapy

M. Nowak

¹Pathophysiology Division, Department of Pathophysiology and Endocrinology

,

B. Marek

¹Pathophysiology Division, Department of Pathophysiology and Endocrinology

,

J. Karpe

³Department of Anaesthesiology and Intensive Therapy, School of Medicine with Division of Density, Medical University of Silesia, Zabrze, Poland

,

B. Kos-Kudla

²Endocrinology Division, Department of Pathophysiology and Endocrinology

,

L. Sieminska

¹Pathophysiology Division, Department of Pathophysiology and Endocrinology

,

D. Kajdaniuk

¹Pathophysiology Division, Department of Pathophysiology and Endocrinology

,

M. Treszer

⁴Department of Internal Medicine with Intensive Care Unit, SPZOZ Hospital in Brzesko, Poland

› Author Affiliations

Abstract

Introduction: Thyroid orbitopathy (TO) is the most frequent extrathyroid manifestation of Graves’ disease. The aim of this study was to evaluate the serum concentration of Vascular Endothelial Growth Factor (VEGF), Plated-Derived Growth Factor-AA (PDGF-AA) in the blood of patients with active OT before and after immunosuppressive therapy.

Patients and Methods: The study was performed in group of 39 patients with clinically active TO (Group A) in euthyroid (n=18, Group A I) and hyperthyroid (n=21, Group A II) stage of Graves’ disease in moderate or severe stage of TO. Control group consist of 20 healthy age-matched control subjects. Concentration of studied proangiogenic factors in serum samples were measured by an enzyme linked immunosorbent assay (ELISA) before (group A) and after (group A1) intensive pulse methylprednisolone treatment and one month after the end of additional oral methylprednisolone treatment (Group A2).

Results: We have found significant increased serum levels of VEGF in patients with TO (regardless to treatment) when compared with control group (542.4±328.1 pg/ml vs. 94.6±55.3 pg/ml, p=0.0002) and increased serum levels of PDGF-AA in patients before treatment (3 173.6±1 480.3 pg/ml) in comparison with controls (1 768.9±520.0 pg/ml) and patients after intensive pulse methyloprednisolone treatment (2 325.9±1 456.8 pg/ml). One month after the end of additional oral methylprednisolone treatment (Group A2) concentration of PDGF-AA still decreased and were was not significant difference with value in control group (1 853.1±795.4 vs. 1 769.9±520.0 pg/ml, p=0.99). Serum concentration of VEGF was still significantly higher compared with control. We have not observed difference in serum concentration of studied proangiogenic factors between patients in euthyroid or hyperthyroid stage of Graves’ disease.

Conclusions: Results of the present study confirm the fact that angiogenesis could play a role in pathogenesis of thyroid orbitopathy.

Key words

Graves’ orbitopathy - proangiogenic factors - methylprednisolone treatment

Full Text

References

References
1 Lazarus JH. Epidemiology of Graves’ orbitopathy (GO) and relationship with thyroid disease. Best Pract Res Clin Endocrinol Metab 2012; 26: 273-279
2 Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid 2002; 12: 855-860
3 Wall JR, Lahooti RS. Pathogenesis of thyroid eye disease – does autoimmunity against the TSH receptor explain all cases?. Endokrynol Pol 2010; 61: 222-227
4 Kumar S, Bahn RS. Relative overexpression of macrophage-derived cytokines in orbital adipose tissue from patients with graves’ ophthalmopathy. J Clin Endocrinol Metab 2003; 88: 4246-4250
5 Gianoukakis AG, Khadavi N, Smith TJ. Cytokines, Graves’ disease, and thyroid-associated ophthalmopathy. Thyroid 2008; 18: 953-958
6 Khalilzadeh O, Anvari M, Momen-Heravi F et al. Gene polymorphisms of interleukin-4, interleukin-10 and transforming growth factor-beta in Graves’ disease. Clin Exp Med 2010; 10: 123-128
7 Myśliwiec J, Palyga I, Nikołajuk A et al. Serum interleukin-16 and RANTES during treatment of Graves’ orbitopathy with corticosteroids and teleradiotherapy. Endokrynol Pol 2012; 63: 92-96
8 Medina J, Arroyo AG, Sanchez-Madrid F et al. Angiogenesis in Chronic Inflammatory Liver Disease. Hepatol 2004; 39: 1185-1195
9 Chaparro M, Sanz-Cameno P, Trapero-Marugan M et al. Mechanisms of angiogenesis in chronic inflammatory liver disease. Ann Hepatol 2007; 6: 208-213
10 Carmeliet P. Angiogenesis in health and disease. Nat Med 2003; 9: 653-660
11 Goth MI, Hubina E, Raptis S et al. Physiological and pathological angiogenesis in the endocrine system. Microsc Res Tech 2003; 60: 98-106
12 Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992; 267: 10931-10934
13 Perez-Lopez M, Sales-Sanz M, Robolleda G et al. Retrobulbar ocular blood flow changes after orbital decompression in Graves’ ophthalmopathy measured by color Doppler imaging. Invest Ophthalmol Vis Sci 2011; 52: 5612-5617
14 Kajdaniuk D, Marek B, Borgiel-Marek H et al. Transforming growth factor beta1 (TGFbeta1) in physiology and pathology. Endokrynol Pol 2013; 64: 384-396
15 Bartalena L, Baldeschi L, Dickinson AJ et al. Consensus statement of the European Group on Graves’ Orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Eur J Endocrinol 2008; 158: 273-285
16 Król A, Koehler A, Nowak M et al. Radioactive iodine (RIA) treatment of hyperthyroidism is safe in patients with Graves’ orbitopathy – a prospective study. Endokrynol Pol 2014; 65: 40-45
17 Brown LF, Berse B, Jackman RW et al. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 1993; 143: 1255-1262
18 Brown LF, Berse B, Jackman RW et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 1993; 53: 4727-4735
19 Brown LF, Berse B, Jackman RW et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 1995; 26: 86-91
20 Fukumura D, Xavier R, Sugiura T. Tumor induction of VEGF promoter activity in stromal cells. Cell 1998; 94: 715-725
21 Ferrara N, Gerber H, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-676
22 Kraft A, Weindel K, Ochs A et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer 1999; 85: 178-187
23 Fenton C, Patel A, Dinauer C et al. The expression of vascular endothelial growth factor and the type 1 vascular endothelial growth factor receptor correlate with the size of papillary thyroid carcinoma in children and young adults. Thyroid 2000; 10: 349-357
24 Ramsden JD. Angiogenesis in the thyroid gland. J Endocrinol 2000; 166: 475-480
25 Jebreel A, England J, Bedford K et al. Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. Int J Exp Path 2007; 88: 271-277
26 Iitaka M, Miura S, Yamanaka K et al. Increased serum vascular endothelial growth factor levels and intrathyroidal vascular area in patients with Graves’ disease and Hashimoto’s thyroiditis. J Clin Endocrinol Metab 1998; 83: 3908-3912
27 Nagura S, Katoh R, Miyagi E et al. Expression of vascular endothelial growth factor (VEGF) and VEGF receptor-1 (Flt-1) in Graves disease possibly correlated with increased vascular density. Hum Pathol 2001; 32: 10-17
28 Turner HE, Harris AL, Melmed S et al. Angiogenesis in endocrine tumors. Endocr Rev 2003; 24: 600-632
29 Sato K, Yamazaki K, Shizume K et al. Stimulation by thyroid-stimulating hormone and Grave’s immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo. J Clin Invest 1995; 96: 1295-1302
30 Matos K, Manso PG, Marback E et al. Protein expression of VEGF, IGF-1 and FGF in retroocular connective tissues and clinical correlation in Graves’ ophthalmopathy. Arq Bras Oftalmol 2008; 71: 486-492
31 Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 1999; 18: 6853-6866
32 Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 2004; 15: 255-273
33 van Steensel L, Paridaens D, Schrijver B et al. Imatinib mesylate and AMN107 inhibit PDGF-signaling in orbital fibroblasts: a potential treatment for Graves’ ophthalmopathy. Invest Ophthalmol Vis Sci 2009; 50: 3091-3098
34 van Steensel L, Paridaens D, Dingjan GM et al. Platelet-Derived Growth Factor-BB: A Stimulus for Cytokine Production by Orbital Fibroblasts in Graves’ Ophthalmopathy. Invest Ophthalmol Vis Sci 2010; 51: 1002-1007
35 van Steensel L, Hooijkaas H, Paridaens D et al. PDGF enhances orbital fibroblast responses to TSHR stimulating autoantibodies in Graves’ ophthalmopathy patients. J Clin Endocrinol Metab 2012; 97: 944-953