Expression of VEGF receptors in normal and adenomatous human pituitary

Abstract

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and exerts its action through different tyrosine kinase receptors: VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR) and neuropilin-1, a co-receptor of VEGFR-2, which are almost specifically expressed in endothelial cells and VEGFR-3 (Flt-4), which is detected mainly in lymphatic vessels. However, it has been shown that VEGF receptors may also be expressed by non-endothelial cells, especially by tumor cells. We have observed that pituitary adenoma cells produce variable amounts of VEGF and have studied the expression of VEGF receptors in normal human pituitary and pituitary adenomas by RT-PCR and immunohistochemistry. Protein expression of VEGFR-1, VEGFR-2, VEGFR-3 and neuropilin-1 was found in normal pituitary and in the pituitary adenomas studied so far. The expression was variable and no correlation between VEGFR-1 and VEGFR-2 expression and different parameters as tumor grade, vessels number and proliferation index (PI) was found. In normal pituitary, VEGFR-1 immunoreactivity was observed to co-localize with ACTH-, FSH-, GH- and LH- secreting cells, but not with endothelial cells, suggesting that VEGF may affect function of endocrine cell types by paracrine mechanisms. Moreover, VEGFR-1 immunostaining was observed mainly in pituitary adenoma cells. In contrast, VEGFR-2, VEGFR-3 and neuropilin-1 immunoreactivity was detected only in vascular formations, in both normal pituitary and pituitary adenomas and interestingly, we observed a correlation between neuropilin-1 expression and vessel count and proliferation index of the tumors analyzed. This finding could be consistent with the observation that neuropilin-1 acts as a co-receptor for VEGFR-2, enhancing the activity of VEGF. According on its receptors localization, VEGF seems to have a role both on tumor cells and on tumor vessels, even if not directly on vessel proliferation. Further studies are anyway necessary to better understand the possible connection between VEGF and its receptors and pituitary adenomas development.