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Advanced glycation end products (AGEs) are compounds formed by irreversible glycation of proteins. Our research group has recently demonstrated that high-molecular-weight AGEs (HMW-AGEs) impair cardiac function in healthy rats. This project aims to examine the effect of HMW-AGEs on vascular function and to investigate ultrastructural abnormalities in cardiomyocytes. Therefore, male Sprague Dawley rats were daily intraperitoneally injected with either HMW-AGEs or a control solution for six weeks. Plasma AGEs levels and cardiac hemodynamic parameters were evaluated to validate this animal model. The relaxation responses to cumulative doses of acetylcholine (ACh) or sodium nitroprusside (SNP) were assessed in isolated rat aortic rings. Microscopy was performed to examine the ultrastructural cardiomyocyte organization. HMW-AGEs injections in rats significantly increased plasma AGEs levels and cardiac pressure. The vasorelaxation response to ACh but not to SNP was decreased in HMW-AGEs animals, indicating impaired endothelium-dependent relaxation. Interestingly, superoxide dismutase restored relaxation in aortic rings from HMW-AGEs animals, which indicates that HMW-AGEs disturb vascular function through superoxide formation. In addition, we show that HMW-AGEs cause ultrastructural remodeling in cardiomyocytes, characterized by an increase in cytoplasmic fraction and a reduction of mitochondrial area and number in cardiomyocytes. This research provides more insight into the role of HMW-AGEs in cardiovascular disease.