Time-Dependent Effect of Orchidectomy on Vascular Nitric Oxide and Thromboxane A2 Release. Functional Implications to Control Cell Proliferation through Activation of the Epidermal Growth Factor Receptor

Abstract

This study analyzes whether the release of nitric oxide (NO) and thromboxane A2 (TXA2) depends on the time lapsed since gonadal function is lost, and their correlation with the proliferation of vascular smooth muscle cells (VSMC) mediated by the epidermal growth factor receptor (EGFR). For this purpose, aortic and mesenteric artery segments from control and 6-weeks or 5-months orchidectomized rats were used to measure NO and TXA2 release. The results showed that the basal and acetylcholine (ACh)-induced NO release were decreased 6 weeks post-orchidectomy both in aorta and mesenteric artery, but were recovered 5 months thereafter up to levels similar to those found in arteries from control rats. The basal and ACh-induced TXA2 release increased in aorta and mesenteric artery 6 weeks post-orchidectomy, and was maintained at high levels 5 months thereafter. Since we previously observed that orchidectomy, which decreased testosterone level, enlarged the muscular layer of mesenteric arteries, the effect of testosterone on VSMC proliferation was analyzed. The results showed that treatment of cultured VSMC with testosterone downregulated mitogenic signaling pathways initiated by the ligand-dependent activation of the EGFR. In contrast, the EGFR pathways were constitutively active in mesenteric arteries of long-term orchidectomized rats. Thus, the exposure of mesenteric arteries from control rats to epidermal growth factor (EGF) induced the activation of EGFR signaling pathways. However, the addition of EGF to arteries from orchidectomized rats failed to induce a further activation of these pathways. In conclusion, this study shows that the release of NO depends on the time lapsed since the gonadal function is lost, while the release of TXA2 is already increased after short periods post-orchidectomy. The alterations in these signaling molecules could contribute to the constitutive activation of the EGFR and its downstream signaling pathways after long period post-orchidectomy enhancing the proliferation of the vascular muscular layer.

Docosahexaenoic Acid Supplemented Diet Influences the Orchidectomy-Induced Vascular Dysfunction in Rat Mesenteric Arteries

“…The results now presented are in agreement with these previous findings, since TXA 2 , PGI 2 , and PGE 2 are increased from the 6 week post-orchidectomy, as observed in aorta [24] and in mesenteric artery for the case of TXA 2 [32]. However, DHA-supplemented diet decreased prostanoids release near to the control group levels.…”

“…NO release was decreased by castration, as reported earlier in aortas from 6 weeks post-orchidectomized rats [32, 24]. The influence of the DHA-supplemented diet, showed a restoration in NO release levels, closely to the ones from the control group, as previously found in aorta [24].…”

Effect of Dietary Docosahexaenoic Acid Supplementation on the Participation of Vasodilator Factors in Aorta from Orchidectomized Rats

“…We have previously demonstrated that the release of prostanoids was increased 5 months post-orchidectomy in aorta and mesenteric arteries [ 21 – 23 , 25 ], most likely as a consequence of increased oxidative stress observed in these experimental conditions. In the present study we show that in aorta from 6 weeks post-orchidectomized rats the ACh-induced release of PGI 2 , PGF 2α and PGE 2 were already increased, as observed for TXA 2 release in a previous study [ 28 ]. These results showed that the loss of gonadal function favored the onset of a pro-inflammatory environment.…”

“…Regarding the production of NO, quantified by measuring nitrite production and the fluorescence emitted by DAF-2, the current study shows that it was decreased in aortas from 6 weeks post-orchidectomized rats, according to previously published [ 28 ], while in aortas from orchidectomized rats fed a DHA-supplemented diet the NO production was restored. These results are in line with other studies describing increase in NO release by n-3 PUFA [ 38 – 40 ].…”

“…On the other hand, it is well established that sex hormones regulate vascular function by altering the release and cell signaling pathways of endothelial factors that could lead to vascular dysfunction. In this regard, we have demonstrated that the loss of gonadal function modifies the production of vasoconstrictor prostanoids [ 21 – 24 ], superoxide anion [ 25 – 27 ] and NO [ 28 ]. Since the number of vascular pathologies matching with decreased levels of sex hormones is increasing [ 29 , 30 ], it would be of interest investigate whether a DHA-supplemented diet could prevent vascular changes induced when an impaired gonadal function exist (i.e.…”