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Dopaminergic D2 receptor knockout mouse: an animal model of prolactinoma
Carolina Cristina1, Isabel García-Tornadú, Graciela Díaz-Torga
1Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.
Abstract:
Dopamine receptor type 2 (D2R) knockout mice (KO) have chronic hyperprolactinemia, pituitary hyperplasia, and a moderate decrease in MSH content. They are also growth retarded evidencing an alteration in the GH-IGF-I axis. In D2R KO, lactotropes do not show dense secretory granules but degranulated cells and fewer somatotropes, gonadotropes and thyrotropes. Prolactin levels are always higher in female than in male knockouts, 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. Prominent vascular channels in the hyperplastic and adenomatous pituitaries, as well as extravasated red blood cells not contained in capillaries is also a common finding. Prolactin is not the factor that enhances the hyperplastic phenotype in females while estrogen is a permissive factor. VEGF-A expression is increased in pituitaries from D2R KO. VEGF-A is expressed in follicle stellate cells. Because D2R receptors are found in lactotropes and not in follicle stellate cells, it may be inferred that a paracrine-derived factor from lactotropes is acting on follicle stellate cells to increase VEGF-A expression. VEGF-A does not induce pituitary cell proliferation, even though it enhances prolactin secretion. But it may act on adjacent endothelial cells and participate in the angiogenic process that increases the availability of different growth factors and mitogens. 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.
Insights
Dopamine receptor type 2 knockout mice develop pituitary tumors and hyperplasia, particularly females. Vascular endothelial growth factor-A (VEGF-A) is implicated in pituitary adenoma development and may be a therapeutic target.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Dopamine receptor type 2 (D2R) knockout mice exhibit chronic hyperprolactinemia, pituitary hyperplasia, and altered growth hormone (GH)-insulin-like growth factor I (IGF-I) axis.
- D2R knockout pituitaries show degranulated lactotropes and reduced numbers of somatotropes, gonadotropes, and thyrotropes.
- Female D2R knockout mice develop pituitary hyperplasia and highly vascularized adenomas with age, suggesting a role for estrogen.
Purpose of the Study:
- To investigate the mechanisms underlying pituitary hyperplasia and adenoma formation in D2R knockout mice.
- To explore the role of vascular endothelial growth factor-A (VEGF-A) in pituitary pathology in D2R knockout mice.
- To evaluate the potential of VEGF-A as a therapeutic target for dopamine-resistant prolactinomas.
Main Methods:
- Characterization of pituitary morphology and cell populations in D2R knockout mice.
- Assessment of prolactin levels and hormonal axis alterations.
- Analysis of VEGF-A expression and its localization within the pituitary gland.
Main Results:
- D2R knockout mice exhibit significant hyperprolactinemia and pituitary hyperplasia, with adenomas forming in older females.
- VEGF-A expression is upregulated in D2R knockout pituitaries, localized to follicle stellate cells, suggesting paracrine signaling.
- VEGF-A enhances prolactin secretion and promotes angiogenesis, potentially contributing to adenoma growth and vascularization.
Conclusions:
- The D2R knockout mouse is a valuable model for studying dopamine-resistant prolactinomas.
- VEGF-A plays a crucial role in the angiogenic process within hyperplastic and adenomatous pituitaries.
- VEGF-A inhibition represents a potential therapeutic strategy for prolactinomas.
