CONICET | Buscador de Institutos y Recursos Humanos

Dopamine type 2 receptor (D2R) knockout mice (KO) have chronic hyperprolactinemia, and pituitary hyperplasia. They are also growth retarded evidencing and alteration in the GH-IGF-I axis. In D2R KO mice prolactin levels are always higher in female than in males, and in accordance, pituitary hyperplasia is observed at 8 months only in females. After 16 months of age highly vascularized adenomas develop, especially in females, but also in males. Prominent vascular channels in the hyperplastic and adenomatous pituitaries, as well as extravasated red blood cells not contained in capillaries are also common findings. High serum prolactin is not the factor that enhances the hyperplastic phenotype in females while estrogens have a permissive action. We studied the participation of angiogenic factors in this animal model of resistant prolactinomas. VEGF-A expression was increased in pituitaries from D2R KOs, and expressed in folliclestellate cells. Because D2R are found in lactotropes and not in folliclestellate cells it may be inferred that a paracrine-derived factor from lactotropes is acting on folliclestellate cells to increase VEGF-A expression. VEGF-A did not induce pituitary cell proliferation, even though it enhanced prolactin secretion. Nevertheless, it increases the proliferation of endothelial cells and may participate in the angiogenic process that increases the availability of different growth factors and mitogens to the gland. Pttg and FGF-2, on the other hand were decreased in the hyperplastic pituitary, in relation to the relatively benign nature of these tumors. The D2R knockout mouse represents a unique animal model to study dopamine-resistant prolactinomas, and VEGF-A may be an alternative therapeutic target in this pathology