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.
Highlights
The vascular tone is regulated by several mechanisms that implicate the participation of hormonal, neuronal and endothelial factors [1]
Clinical studies have shown a correlation between hypotestosteronemia and incidence of cardiovascular diseases [5] and mortality risk [6]. These issues, as well as different mechanisms of action by which testosterone causes vasodilation were reviewed by Jones [7], In this regard, previous studies from our group have demonstrated an increase in the production of superoxide anion [8], prostanoids, such as thromboxane A2 (TXA2) [9,10] and prostaglandin E2 (PGE2) [11] five months post-orchidectomy
Concerning the effects of sex hormones deprivation on vascular function, we previously demonstrated in mesenteric artery of orchidectomized rats that the increased activity of protein kinase C (PKC) positively regulated eNOS activity [19], preventing a decrease in the release of endothelial nitric oxide (NO)
Summary
The vascular tone is regulated by several mechanisms that implicate the participation of hormonal, neuronal and endothelial factors [1]. Clinical studies have shown a correlation between hypotestosteronemia and incidence of cardiovascular diseases [5] and mortality risk [6] These issues, as well as different mechanisms of action by which testosterone causes vasodilation were reviewed by Jones [7], In this regard, previous studies from our group have demonstrated an increase in the production of superoxide anion [8], prostanoids, such as thromboxane A2 (TXA2) [9,10] and prostaglandin E2 (PGE2) [11] five months post-orchidectomy. Androgen-induced relaxation has been reported to be mediated by endothelium-independent mechanisms [18] This variety of results could depend on the tissue, the concentration, administrationtime, and the molecular structure of the androgenic derivatives used
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