RESUMEN
The antiulcer drug cimetidine has shown to cause changes in the testicular microvasculature of adult rats. Since Leydig cells (LCs) produce the pro-angiogenic factor, EG-VEGF (endocrine gland-derived vascular endothelial growth factor), also known as prokineticin 1 (PK-1), this study examined the effect that cimetidine might have on LCs in testes with damaged vasculature. Rats received intraperitoneal injections of 100mg/kg of cimetidine (cimetidine group) or saline vehicle (control group) for 50 days. Serum testosterone levels were measured by chemiluminescence immunoassay and testicular sections were subjected to TUNEL and immunohistochemical reactions for caspase-3, 17ß-HSD6, CD163 (ED2 macrophage), PK-1 and androgen receptor (AR). LCs in the cimetidine group showed TUNEL and caspase-3 positive labeling and apoptotic ultrastructural features. Moreover, the presence of 17ß-HSD6-positive inclusions inside macrophages and the reduced number of LCs, AR immunoreactivity and serum testosterone levels correlated with a decrease in either the number of PK-1-immunostained LCs or PK-1 immunoreactivity. Although it is not clear which cell type is the primary target of cimetidine in the testicular interstitial compartment, these findings support a direct link between cimetidine-induced testicular vascular atrophy and LCs damage.
Asunto(s)
Antiulcerosos/toxicidad , Cimetidina/toxicidad , Testículo/efectos de los fármacos , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Apoptosis/efectos de los fármacos , Atrofia , Caspasa 3/metabolismo , Masculino , Microscopía Electrónica de Transmisión , Ratas , Receptores Androgénicos/metabolismo , Receptores de Superficie Celular/metabolismo , Testículo/metabolismo , Testículo/patología , Testículo/ultraestructura , Testosterona/sangre , Factor de Crecimiento Endotelial Vascular Derivado de Glándula Endocrina/metabolismoRESUMEN
The prokineticin system comprises two multifunctional secreted proteins, prokineticin-1 (PROK1) and prokineticin-2 (PROK2), and their cognate G protein-coupled receptors. The prokineticins were originally identified as endogenous regulators of gastrointestinal motility. Currently, these bioactive peptides are involved in a wide spectrum of biological functions, including angiogenesis, neurogenesis, circadian rhythms, nociception, hematopoiesis and immune response. Mice homozygous for null mutations in Prokr2 or Prok2 recapitulate the human phenotype of Kallmann syndrome, exhibiting severe atrophy of the reproductive system and hypoplastic olfactory bulbs. Indeed, the evidence from several naturally inactivating mutations in the PROK2 and PROKR2 genes in patients with Kallmann syndrome and normosmic hypogonadotropic hypogonadism also indicate the essential role of PROK2 in olfactory bulb morphogenesis and GnRH secretion in humans.
Asunto(s)
Hormonas Gastrointestinales/genética , Hipogonadismo/genética , Neuropéptidos/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos/genética , Factor de Crecimiento Endotelial Vascular Derivado de Glándula Endocrina/genética , Animales , Femenino , Hormonas Gastrointestinales/metabolismo , Humanos , Hipogonadismo/metabolismo , Masculino , Ratones , Mutación , Neuropéptidos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Péptidos/metabolismo , Factor de Crecimiento Endotelial Vascular Derivado de Glándula Endocrina/metabolismoRESUMEN
Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) was recently identified as the first tissue-specific angiogenic molecule. EG-VEGF (the gene product of PROK-1) appears to be expressed exclusively in steroid-producing organs such as the ovary, testis, adrenals and placenta. Since the human pancreatic cells retain steroidogenic activity, in the present study we ascertained whether this angiogenic factor is expressed in normal pancreas and pancreatic adenocarcinoma. Tissue samples from normal males (n=5), normal females (n=5) and from surgically resected adenocarcinomas (n=2) were processed for RT-PCR and immunohistochemical studies. Results from semi-quantitative analysis by RT-PCR suggest a distinct expression level for EG-VEGF in the different tissue samples. The relative amount of EG-VEGF mRNA in pancreas was more abundant in female adenocarcinoma (0.89) followed by male adenocarcinoma (0.71), than normal female (0.64) and normal male (0.38). The expression of mRNA for EG-VEGF in normal tissue was significantly higher in females than in males. All samples examined showed specific immunostaining for EG-VEGF. In male preparations, the positive labeling was localized predominantly within the pancreatic islets while in female preparations the main staining was detected towards the exocrine portion. Specific immunolabeling was also observed in endothelial cells of pancreatic blood vessels. Our data provide evidence that the human pancreas expresses the EG-VEGF, a highly specific mitogen which regulates proliferation and differentiation of the vascular endothelium. The significance of this finding could be interpreted as either, EG-VEGF is not exclusive of endocrine organs, or the pancreas should be considered as a functional steroidogenic tissue. The extent of the expression of EG-VEGF appears to have a dimorphic pattern in normal and tumoral pancreatic tissue.