Angiotensin II enhances endothelin-1-induced vasoconstriction through upregulating endothelin type A receptor |
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Authors: | Yan-Jie Lin Ching-Fai Kwok Chi-Chang Juan Yung-Pei Hsu Kuang-Chung Shih Chin-Chang Chen Low-Tone Ho |
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Institution: | 1. Institute of Physiology, National Yang-Ming University, Taipei, Taiwan;2. Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;3. Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan;4. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan |
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Abstract: | Endothelin-1 (ET-1) is the most potent vasoconstrictor by binding to endothelin receptors (ETAR) in vascular smooth muscle cells (VSMCs). The complex of angiotensin II (Ang II) and Ang II type one receptor (AT1R) acts as a transient constrictor of VSMCs. The synergistic effect of ET-1 and Ang II on blood pressure has been observed in rats; however, the underlying mechanism remains unclear. We hypothesize that Ang II leads to enhancing ET-1-mediated vasoconstriction through the activation of endothelin receptor in VSMCs. The ET-1-induced vasoconstriction, ET-1 binding, and endothelin receptor expression were explored in the isolated endothelium-denuded aortae and A-10 VSMCs. Ang II pretreatment enhanced ET-1-induced vasoconstriction and ET-1 binding to the aorta. Ang II enhanced ETAR expression, but not ETBR, in aorta and increased ET-1 binding, mainly to ETAR in A-10 VSMCs. Moreover, Ang II-enhanced ETAR expression was blunted and ET-1 binding was reduced by AT1R antagonism or by inhibitors of PKC or ERK individually. In conclusion, Ang II enhances ET-1-induced vasoconstriction by upregulating ETAR expression and ET-1/ETAR binding, which may be because of the AngII/Ang II receptor pathways and the activation of PKC or ERK. These findings suggest the synergistic effect of Ang II and ET-1 on the pathogenic development of hypertension. |
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Keywords: | Ang II angiotensin II ET-1 endothelin-1 ETAR endothelin type A receptor ETBR endothelin type B receptor AT1R angiotensin II type 1 receptor AT2R angiotensin II type 2 receptor PKC protein kinase C ERK extracellular signal-regulated kinase |
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