Translation from mice to monkeys toward human: species differences in endothelial-dependent vasorelaxation in various...

Compounds inducing effects on the blood pressure may act on arteries. The endothelium is frequently involved in these vascular effects, and its influence may depend on vascular beds and species, making translational interpretation challenging. This study aimed to assess the endothelial responses and reactivity across various vascular beds from different animal species (rats, mice and monkeys) and human. Endothelium-dependent vasorelaxation due to acetylcholine in large and resistance arteries from healthy rats, mice, monkeys and human were evaluated using isolated organ bath or wire myography. Contraction induced by serotonin have been also investigated in various human vessels. Mice aorta, but not mesenteric arteries, was more sensitive to acetylcholine compared to rat arteries. Monkey abdominal aorta displayed a weak relaxation, whereas a potent relaxation was observed in mammary, mesenteric and subcutaneous arteries. Human and monkey subcutaneous arteries exhibited similar vasorelaxations. Interesting, human veins exhibited potent contraction to serotonin compared to resistance and large arteries. Overall, resistance arteries were more sensitive and responsive to endothelial stimulation by acetylcholine, compared to large arteries. This study provides evidences of the variability of endothelium-dependent vasorelaxant responses across various vascular beds and species. This work underlines the importance of selecting the most appropriate vascular bed and species based on the scientific /pharmacological rationales (molecular target, in vivo pharmacodynamic, therapeutic indication and target organ) to enable a translational interpretation of findings.