Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging

Abstract

<jats:p>Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide–cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1Δ/- mice, can be used as a tool to accelerate aging. Ercc1Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO–cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1Δ/- mice. Ercc1Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1Δ/- mice developed decreased reactive hyperemia, and diminished NO–cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO–cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.</jats:p>

Selective Phosphodiesterase 1 Inhibition Ameliorates Vascular Function, Reduces Inflammatory Response, and Lowers Blood Pressure in Aging Animals

“…Chronic ITI-214 improved endothelium-independent vasodilation in the aorta, coronary artery, and the cutaneous microcirculation of Ercc1 Δ/mice, suggesting that PDE1 is relevant for a large array of arteries. In the aorta, we have used a single high dose of SNP after ACh CRC, since we know from previous studies that the maximum response to this single high dose of SNP after the ACh CRC duplicates the maximum reached after a full SNP CRC (Golshiri et al, 2020). Acute administration of ITI-214 to the organ bath yielded no further SNP response in rings of ITI-214-treated mice (data not shown), supporting that ITI-214 was still present in the aortic rings after isolation.…”

“…The two-mm coronary segments were also mounted following the same procedure, the maximum contractile responses were determined using 60 mmol/L KCl, and CRCs to ACh and SNP were performed after preconstriction with 30 nmol/L U46619. L-NAME 100 μmol/L, TRAM34 10 μmol/L, and apamin 100 nmol/L were given 10 minutes before U46619, to investigate the involvement of nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) pathway in the relaxation responses (Golshiri et al, 2020). To assess the acute effects of PDE1 inhibition, 100 nmol/L ITI-214 was added to the organ bath 15 minutes before preconstriction.…”

“…The in vivo blood pressure was measured in conscious animals by an experienced technician, using the tail-cuff technique (CODA High-Throughput device from Kent Scientific) after 5 daily sessions: 4 training sessions and a subsequent measurement session to record 40 measurement cycles. The average of the valid cycles was used for comparison (Golshiri et al, 2020).…”

“…Unlike risk factors such as dyslipidemia and hypertension, for which suitable models exist to study their primary risk contributions to vascular dysfunction and response to prevention or intervention maneuvers, ageing lacks such models and has thus been harder to study. This limitation was recently overcome by the discovery that accumulating DNA damage is a central causative mechanism for ageing, along with the development of accelerated ageing mouse models based on genetically reduced DNA repair (Wu et al, 2017;Golshiri et al, 2020). In several of these models, risk factor-free accelerated vascular ageing was demonstrated.…”

“…The model has been used as a convenient tool to test the effects of dietary and pharmacological interventions. We have used this model to explore mechanisms of aberrant nitric oxide (NO) -cGMP signaling in smooth muscle cells, which plays a central role in vascular ageing (Wu et al, 2017;Golshiri et al, 2020).…”