Nitric oxide up-regulates endothelial expression of angiotensin II type 2 receptors

Vu Thao-Vi Dao, Sawsan Medini, Marion Bisha, Vera Balz, Tatsiana Suvorava, Murat Bas, Georg Kojda*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Increasing vascular NO levels following up-regulation of endothelial nitric oxide synthase (eNOS) is considered beneficial in cardiovascular disease. Whether such beneficial effects exerted by increased NO levels include the vascular renin-angiotensin system remains elucidated. Exposure of endothelial cells originated from porcine aorta, mouse brain and human umbilical veins to different NO-donors showed that expression of the angiotensin-II-type-2-receptor (AT2) mRNA and protein is up-regulated by activation of soluble guanylyl cyclase, protein kinase G and p38 mitogen-activated protein kinase without changing AT2 mRNA stability. In mice, endothelial-specific overexpression of eNOS stimulated, while chronic treatment with the NOS-blocker L-nitroarginine inhibited AT2 expression. The NO-induced AT2 up-regulation was associated with a profound inhibition of angiotensin-converting enzyme (ACE) activity. In endothelial cells this reduction of ACE-activity was reversed by either the AT2 antagonist PD 123119 or by inhibition of transcription with actinomycin D. Furthermore, in C57BI/6 mice an acute i.v. bolus of L-nitroarginine did not change AT2-expression and ACE-activity suggesting that inhibition of ACE-activity by endogenous NO is crucially dependent on AT2 protein level. Likewise, three weeks of either voluntary or forced exercise training increased AT2 expression and reduced ACE-activity in C57BI/6 but not in mice lacking eNOS suggesting significance of this signaling interaction for vascular physiology. Finally, aortic AT2 expression is about 5 times greater in female as compared to male C57B1/6 and at the same time aortic ACE activity is reduced in females by more than 50%. Together these findings imply that endothelial NO regulates AT2 expression and that AT2 may regulate ACE-activity.
Original languageEnglish
Pages (from-to)24-36
JournalBiochemical Pharmacology
Publication statusPublished - 15 Jul 2016


  • Nitric oxide
  • Endothelial nitric oxide synthase
  • Exercise
  • Angiotensin II type 2 receptor
  • Angiotensin converting enzyme 1


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