Captopril alleviates vascular endothelial dysfunction by regulating TRPV1 and activating the eNOS pathway.

BACKGROUND

Vascular endothelial dysfunction (VED) underlies the pathogenesis of diabetic cardiovascular complications. Captopril (CAP), an angiotensin-converting enzyme inhibitor widely used in clinical practice, remains poorly understood in terms of its ability to alleviate diabetic VED.

METHODS

Key CAP- and VED-associated targets were identified through network pharmacology. In vivo, the effects of CAP on vascular permeability, nitric oxide (NO) levels, and reactive oxygen species (ROS) were evaluated in diabetic rats. In vitro, C166 cells exposed to high glucose were treated with CAP, with or without TRPV1 antagonist pretreatment, to assess TRPV1/eNOS expression and endothelial function.

RESULTS

Network pharmacology and protein-protein interaction (PPI) analyses identified eNOS, HSP90A, and PPARG as central targets. In vivo, CAP improved vascular permeability, reduced ROS levels, and increased NO production, accompanied by increased TRPV1 and eNOS expression. In vitro, CAP restored TRPV1/eNOS expression, elevated NO levels, mitigated oxidative stress, and enhanced endothelial barrier function. Notably, TRPV1 inhibition abolished these protective effects.

CONCLUSION

This study predicted potential targets and pathways through which CAP may act on VED. For the first time, CAP was shown to alleviate diabetic VED in a TRPV1-dependent manner by activating the TRPV1/eNOS pathway, thereby attenuating oxidative stress and restoring endothelial function. These findings highlight CAP as a potential therapeutic agent for mitigating eNOS over-inhibition and endothelial dysfunction in diabetes.