Enhancement of immunoreactivity for endothelin-1 and endothelin-converting enzyme-1 in the cadmium-treated rat thoracic aorta

Abstract

Male rats received daily intraperitoneal injections of cadmium sulfate (2.0 mg/kg) for 3, 6, and 8 days (cadmium-treated groups) or physiological saline for 8 days (control group). The thoracic aortae from both groups were used for electron microscopy and immunocytochemistry for big endothelin (ET)-1, ET-1 and ET-converting enzyme (ECE)-1, and the blood plasma and homogenized thoracic aortae were prepared for assays of big ET-1 and ET-1 concentrations. A remarkable increase in the number of Weibel-Palade (WP) bodies, enhanced immunoreactivities for ET-1 and ECE-1 along the endothelium, and elevated concentrations of ET-1 in the blood plasma as well as in homogenized thoracic aortae were observed in the cadmium-treated groups. However, immunoreactivity for big ET-1 and the plasma and aortic tissue concentrations of big ET-1 did not show any significant changes between the control and cadmium-treated groups. By immunoelectron microscopy, immunoreactivities for ET-1 and ECE-1 were much more pronounced in the increased WP bodies. Since WP bodies are involved in the extracellular release of ET-1 in the manner of a regulated pathway, these findings indicate that cadmium administration induces the enhanced release of ET-1, which is actively processed by ECE-1 in the WP bodies.

Increased Endothelial Exocytosis and Generation of Endothelin-1 Contributes to Constriction of Aged Arteries

“…ET-1 immunofluorescence revealed diffuse punctate staining distinct from VWF suggesting that the primary storage site in native aortic endothelium is in small granules and not WPBs, which is consistent with previous studies in cultured and native endothelium17–22. Under quiescent conditions, there was no significant difference in ET-1 staining between the endothelium of young and aged aortas.…”

“…However, stimulation of cultured endothelial cells also causes a rapid increase in ET-1, which suggests storage of ET-1 or its precursors and regulated exocytosis17. Indeed, ET-1 has been localized to Weibel-Palade bodies (WPBs), the most recognizable endothelial storage granule, although the primary localization in cultured and native endothelium may be in distinct storage granules17–22. This pattern of partial localization in WPBs is similar to other endothelial mediators, including tissue plasminogen activator23–26.…”

Selective ETAR antagonist atrasentan inhibits hypoxia-induced breast cancer cell invasion

“…Later, these secretory vesicles have been found to be identical with the endothelial cell specific storage granules known as Weibel-Palade (WP) bodies [36][37][38]. The involvement of WP bodies in the extracellular release of ET-1 by degranulation/exocytosis has previously been reported in the rat thoracic aorta [39] and the rabbit umbilical vein [40]. Our results indicate that this mechanism may also be of importance in human breast cancer cells since the hypoxia-induced increase of extracellular ET-1 occurred without any change of ET-1 gene transcription.…”

Effect of 5-HT2 Receptor Blockade on Cadmium-Induced Acute Toxicity

“…Possible interactions between cadmium and serotonin and modulation of the vasoactive net effect of the monoamine from the metal are not known but cannot be excluded since they have been observed for other inherent vasoconstrictors as in the case of endothelin [43,44]. It is interesting that the site of action of endothelin in the vascular bed is at the sinusoidal level beyond the arterioles, and cadmium could also act at these points, inducing ischemia [45,46].…”