Reduced nitric oxide (NO)/cGMP signalling is observed in age-related vascular disease. We hypothesize that this disturbed signalling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells (VSMCs) and that the underlying mechanism plays a role in human age-related vascular disease. To test our hypothesis, we combined experiments in mice with genomic instability resulting from the defective nucleotide excision repair gene ERCC1 (Ercc1(d/-) mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1(d/-) mice showed 43% reduced responses to the soluble guanylate cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNP-relaxing effects in Ercc1(d/-) to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1(d/-) mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1(d/-) mice compared with WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (11.6-, 9- and 2.3-fold respectively), which associated with markers of cellular senescence. Conversely, PDE1 inhibition lowered expression of these markers. Human genetic studies revealed significant associations of PDE1A single nucleotide polymorphisms with diastolic blood pressure (DBP; β=0.28, P=2.47×10(-5)) and carotid intima-media thickness (cIMT; β=-0.0061, P=2.89×10(-5)). In summary, these results show that genomic instability and cellular senescence in VSMCs increase PDE1 expression. This might play a role in aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy.

Cardiovascular Division James Black Centre King's College London SE5 9NU U K

Department of Epidemiology Erasmus MC Rotterdam 3015 CN The Netherlands

Department of Epidemiology University of North Carolina Chapel Hill Chapel Hill NC 27599 7435 U S A

Department of Genetics Erasmus MC Rotterdam 3015 CN The Netherlands

Department of Internal Medicine Division of Endocrinology Erasmus MC Rotterdam 3015 CN The Netherlands

Department of Internal Medicine Division of Vascular Disease and Pharmacology Erasmus MC Rotterdam 3015 CN The Netherlands

Department of Internal Medicine Division of Vascular Disease and Pharmacology Erasmus MC Rotterdam 3015 CN The Netherlands Department of Epidemiology Erasmus MC Rotterdam 3015 CN The Netherlands

Department of Internal Medicine Division of Vascular Disease and Pharmacology Erasmus MC Rotterdam 3015 CN The Netherlands Institute of Molecular Genetics Academy of Sciences of the Czech Republic 142 20 Prague Czech Republic

Department of Pharmacology Maastricht University 6211 LK The Netherlands

Department of Pharmacology Maastricht University 6211 LK The Netherlands Department of Cardiovascular and Renal research Institute of Molecular Medicine University of Southern Denmark 5230 Odense Denmark

National Heart Lung and Blood Institute's Framingham Heart Study Framingham MA 01702 5827 U S A National Heart Lung and Blood Institute Bethesda MD 20892 U S A Cardiology Division Department of Medicine Massachusetts General Hospital Harvard Medical School Boston MA 02114 U S A

Clin Sci (Lond). 2015 Dec;129(12):1077-81. doi: 10.1042/CS20150605. PubMed

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