Co-activation of Mas and pGCA receptors suppresses endothelin-1-induced endothelial dysfunction via nitric oxide/cGMP system

Background: The aortic endothelium is crucial in preserving vascular tone through endothelium-derived vasodilators and vasoconstrictors. Dysfunction in the endothelium is an early indicator of cardiovascular diseases. Our study explores the therapeutic potential of a dual-acting peptide (DAP) to co-activate Mas and pGCA receptors and restore the balance between vasodilators and vasoconstrictors on endothelial dysfunction in DOCA-salt-induced hypertensive rats.

Methods: DOCA-salt was administered to male wistar rats to induce hypertension, and various parameters, including blood pressure (BP), water intake and body weight were monitored. DAP, Ang1-7, BNP, and losartan were administered to hypertensive rats for two weeks. Histological analysis and isometric tension studies were carried out to assess endothelial function. Addition to this we used primary aortic endothelial cells for detailed mechanistic investigations.

Results: DOCA-salt administration significantly elevated systolic, diastolic, mean arterial BP, and water intake whereas, downregulated the gene expression of Mas and pGCA receptors. However, DAP co-administration attenuated BP increase, upregulated the gene expression of Mas and pGCA receptors, normalized serum and urinary parameters, and effectively reduced fibrosis, inflammation, and vascular calcification. Notably, DAP outperformed the standard drug, Losartan. Our findings indicate that DAP restores aortic function by balancing the NO and ET1-induced pathways.

Conclusion: Co-activating Mas and pGCA receptors with DAP mitigates vascular damage and enhances endothelial function, emphasizing its potential to maintain a delicate balance between vasodilatory NO and vasoconstrictor ET1 in endothelial dysfunction.

Endothelial dysfunction; Endothelin 1; Mas receptor; Nitric oxide; eNOS-dependent vasorelaxation; pGCA receptor.