C21 preserves endothelial function in the thoracic aorta from DIO mice: role for AT2, Mas and B2 receptors

Raquel González-Blázquez, Martín Alcalá, María S Fernández-Alfonso, Ulrike Muscha Steckelings, M Paz Lorenzo, Marta Viana, William A Boisvert, Thomas Unger, Marta Gil-Ortega*, Beatriz Somoza

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Compound 21 (C21), a selective agonist of angiotensin II type 2 receptor (AT2R), induces vasodilation through NO release. Since AT2R seems to be overexpressed in obesity, we hypothesize that C21 prevents the development of obesity-related vascular alterations. The main goal of the present study was to assess the effect of C21 on thoracic aorta endothelial function in a model of diet-induced obesity (DIO) and to elucidate the potential cross-talk among AT2R, Mas receptor (MasR) and/or bradykinin type 2 receptor (B2R) in this response. Five-week-old male C57BL6J mice were fed a standard (CHOW) or a high-fat diet (HF) for 6 weeks and treated daily with C21 (1 mg/kg p.o) or vehicle, generating four groups: CHOW-C, CHOW-C21, HF-C, HF-C21. Vascular reactivity experiments were performed in thoracic aorta rings. Human endothelial cells (HECs; EA.hy926) were used to elucidate the signaling pathways, both at receptor and intracellular levels. Arteries from HF mice exhibited increased contractions to Ang II than CHOW mice, effect that was prevented by C21. PD123177, A779 and HOE-140 (AT2R, Mas and B2R antagonists) significantly enhanced Ang II-induced contractions in CHOW but not in HF-C rings, suggesting a lack of functionality of those receptors in obesity. C21 prevented those alterations and favored the formation of AT2R/MasR and MasR/B2R heterodimers. HF mice also exhibited impaired relaxations to acetylcholine (ACh) due to a reduced NO availability. C21 preserved NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways. In conclusion, C21 favors the interaction among AT2R, MasR and B2R and prevents the development of obesity-induced endothelial dysfunction by stimulating NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways.

Original languageEnglish
Pages (from-to)1145-1163
Number of pages19
JournalClinical Science
Issue number9
Publication statusPublished - 14 May 2021


  • Animals
  • Aorta, Thoracic/drug effects
  • Cyclic AMP-Dependent Protein Kinases/metabolism
  • Diet, High-Fat
  • Drug Evaluation, Preclinical
  • Endothelium, Vascular/drug effects
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Imidazoles/pharmacology
  • Male
  • Mice, Inbred C57BL
  • Nitric Oxide/metabolism
  • Nitric Oxide Synthase Type III/metabolism
  • Obesity/complications
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism
  • Receptor Cross-Talk
  • Receptor, Angiotensin, Type 2/agonists
  • Receptor, Bradykinin B2/metabolism
  • Receptors, G-Protein-Coupled/metabolism
  • Renin-Angiotensin System/drug effects
  • Signal Transduction/drug effects
  • Sulfonamides/pharmacology
  • Thiophenes/pharmacology
  • Vascular Diseases/etiology


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