Diminished
nitric oxide-cGMP-mediated relaxation plays a crucial role in cardiovascular aging, leading to decreased vasodilation, vascular
hypertrophy and stiffening, and ultimately, cardiovascular dysfunction. Aging is the time-related worsening of physiologic function due to complex cellular and molecular interactions, and it is at least partly driven by DNA damage. Genetic deletion of the
DNA repair enzyme ERCC1
endonuclease in Ercc1Δ/- mice provides us an efficient tool to accelerate vascular aging, explore mechanisms, and test potential treatments. Previously, we identified the cGMP-degrading
enzyme phosphodiesterase 1 as a potential treatment target in vascular aging. In the present study, we studied the effect of acute and chronic treatment with
ITI-214, a selective
phosphodiesterase 1 inhibitor on vascular aging features in Ercc1Δ/- mice. Compared with wild-type mice, Ercc1Δ/- mice at the age of 14 weeks showed decreased
reactive hyperemia, diminished endothelium-dependent and -independent responses of arteries in organ
baths, carotid wall
hypertrophy, and elevated circulating levels of inflammatory
cytokines. Acute
ITI-214 treatment in organ
baths restored the arterial endothelium-independent vasodilation in Ercc1Δ/- mice. An 8-week treatment with 100 mg/kg per day
ITI-214 improved endothelium-independent relaxation in both aorta and coronary arteries, at least partly restored the diminished
reactive hyperemia, lowered the systolic and diastolic blood pressure, normalized the carotid
hypertrophy, and ameliorated inflammatory responses exclusively in Ercc1Δ/- mice. These findings suggest
phosphodiesterase 1 inhibition would provide a powerful tool for
nitric oxide-cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to aging. SIGNIFICANCE STATEMENT: The findings implicate the key role of
phosphodiesterase 1 in vascular function and might be of clinical importance for the prevention of mortalities and morbidities related to vascular complications during aging, as well as for patients with
progeria that show a high risk of
cardiovascular disease.