Vasoactive intestinal polypeptide (VIP) content is increased in the hyperplastic pituitaries of estrogen (E)-treated rats, thus suggesting that this neuropeptide could mediate the E effect on lactotrophs. E also decreases pituitary TGF-beta1 content, an autocrine/paracrine inhibitor of lactotroph proliferation, and induces pituitary angiogenesis. To elucidate the role of VIP in this context, lactotroph hyperplasia was induced in female Fisher 344 rats by implanting sc pellets of diethylstilbestrol (DES). Twenty-five days later, the rats were treated with three different increasing doses of a VIP receptor antagonist or the vehicle for 5 d. DES treatment resulted in a marked increase of serum prolactin (PRL), pituitary PRL content, PRL mRNA expression, pituitary weight, and pituitary proliferating cell nuclear antigen. DES treatment also increased pituitary VIP content and VIP mRNA levels, but not in the hypothalamus and cerebral cortex. Simultaneously, DES treatment decreased the pituitary TGF-beta1 content and increased the pituitary content of vascular endothelial growth factor. VIP receptor antagonist partially reverted the effect of DES on serum PRL and pituitary PRL, proliferating cell nuclear antigen, TGF-beta1, and vascular endothelial growth factor contents, as well as on pituitary weight, in a dose-dependent relation. These data suggest that pituitary VIP mediates the effect of E on lactotroph hyperplasia, pituitary TGF-beta1, and angiogenesis.
We have shown that pituitary vasoactive intestinal peptide (VIP) mediates the effects of estrogen on lactotrope hyperplasia, angiogenesis and hyperprolactinemia, and reduces the pituitary content of transforming growth factor beta β1 (TGF-β1, an inhibitor of lactotrope proliferation). Dopamine agonists reverse lactotrope hyperplasia and hyperprolactinemia and also reduce the pituitary VIP content in hyperestrogenized rats. To elucidate the interaction of bromocriptine (BC) and pituitary VIP, a VIP receptor antagonist (VA), BC, or both drugs were administered for 5 days to F344 rats treated with diethylstilbestrol (DES). Both BC and VA similarly blocked the effects of DES on pituitary weight and pituitary content of prolactin (PRL), proliferating cell nuclear antigen, and vascular endothelial growth factor, without evidence of synergism. The estrogen effect on pituitary TGF-β1 was completely inhibited by VA, but only partially by BC. On the contrary, serum PRL was close to the normal levels in the BC group 2 h after the first dose, while VA only reduced serum PRL after 5 days. DES increased VIP and VIP mRNA levels specifically at the pituitary, this effect being partially blocked by BC. These data suggest that the dopamine agonists inhibit lactotrope proliferation and angiogenesis by blocking the autocrine/paracrine action of VIP. On the other hand, the dopamine agonists inhibit the estrogen-induced hyperprolactinemia by acting through different pathways than those implicated in the proliferative process.
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