CONICET | Buscador de Institutos y Recursos Humanos

Prolactin secreting adenomas are the most frequent type among pituitary tumors, and pharmacological therapy with dopamine agonists remains the mainstay of treatment. But some are resistant and a decrease in the number or function of dopamine receptor type 2 (D2R) has been described in these cases. D2R knockout (Drd2-/-) mice have chronic hyperprolactinemia, pituitary hyperplasia, and provide an experimental model for dopamine agonist resistant prolactinomas. We previously described that disruption of D2Rs increases pituitary VEGF expression. We therefore designed two strategies of antiangiogenesis using prolactinomas generated in Drd2-/- female mice: 1) direct intra adenoma VEGF-TRAP injection for three weeks (into sc transplanted pituitaries from Drd2-/- mice), and systemic VEGF neutralization with the specific antibody Mab G6-31 in female Drd2-/- 6 month-old mice. Both strategies resulted in substantial decrease of prolactin content and lactotrope area, and a reduction in tumor size was observed in in situ prolactinomas in the second model. There were significant decreases in vascularity, evaluated by CD31 vessel staining (decrease to 43.4 and 49.8 % in CD31 positive vascular area in transplants and in situ pituitaries, P= 0.004 and 0.009, respectively), and proliferation (PCNA staining) in response to both anti-VEGF treatments. These data demonstrate that the antiangiogenic approach was effective in inhibiting the growth of in situ dopamine resistant prolactinomas as well as in the transplanted adenomas. No differences in VEGF protein expression were observed after either anti-VEGF treatment. Our present results indicate that even though the role of angiogenesis in pituitary adenomas is contentious, VEGF might contribute to adequate temporal vascular supply and represent a complementary therapeutic target in aggressive dopamine agonist resistant prolactinomas.