CHANGES IN THE IMMUNOHISTOCHEMICAL LOCALIZATION OF FIBROBLAST GROWTH FACTOR-II, TRANSFORMING GROWTH-FACTOR-BETA-1 AND THROMBOSPONDIN-1 ARE ASSOCIATED WITH EARLY ANGIOGENIC EVENTS IN THE HYPERPLASTIC RAT-THYROID

Administration of a goitrogen (methimazole) and a low iodine diet to r ats over a two-week period resulted in hypothyroidism and thyroid hype rplasia compared with controls (control: total serum thyroxine (T-4) 6 6 +/- 4 nmol/l, thyroid weight 5+/-1 mg/100g body weight; experimental : T-4 undetectable, thyroid weight 27 +/- 4 mg/100 g body weight after 2 weeks of treatment; mean +/- S.D., n=10). Immunohistochemistry carr ied out using a specific endothelial cell marker, CD31, and morphometr ic analysis (point counting of immunopositive cells) revealed that the progression of goitre in the rat thyroid is accompanied by an increas e in capillary endothelial cell growth (neo vascularisation). Fibrobla st growth factor-2 (FGF-2) immunohistochemistry revealed widespread st aining for the protein in the follicular cells of control glands. Less intense staining was found in the stroma and follicular cell nuclei. During hyperplasia and subsequent neovascularisation there was a progr essive increase in the FGF-2 immunoreactivity at all locations during the two-week treatment period. Thrombospondin-1 (TSP1) immunoreactivit y in the control rat thyroid was found in the stroma and in the endoth elial cells, while weak follicular cell staining was also present. In the goitrous rat thyroid the TSP1 immunoreactivity was present after 1 week of treatment in the endothelial cells and most follicular cells, whilst stromal localisation was weak. After week 2 of treatment the e ndothelial cell and stromal localisation was no longer apparent, altho ugh a follicular localisation was:still present. Transforming growth f actor-beta 1 (TGF beta 1) immunoreactivity was present in the cytoplas m of a minority of the follicular cells in control rat thyroids, while ,their nuclei were unstained. In the goitrous rat thyroid an increased intensity of staining for TGF beta 1 was seen in all follicular cells , many of which now also demonstrated immunopositive nuclei, within on e week of goitrogen administration. These results show that in the hyp erplastic thyroid increases in FGF-2 and TGF beta 1, and decreases in TSP1, accompany angiogenesis. These factors may interact in an autocri ne/paracrine relationship to stimulate the neovascularisation that occ urs during goitre formation.