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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 (Ercc1d/− mice), human VSMC cultures and population genome-wide association studies (GWAS). Aortic rings of Ercc1d/− 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 Ercc1d/− to wild-type (WT) levels. PDE1C levels were increased in lung and aorta. cGMP hydrolysis by PDE in lungs was higher in Ercc1d/− mice. No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1d/− 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. [ABSTRACT FROM AUTHOR]

Objective: In heart failure, homologous downregulation of β-adrenoceptors contributes to impaired adrenergic responsiveness of the myocardium. We evaluated α1,-adrenoceptors (α1-AR) in a sparsely innervated and a densely innervated peripheral artery in an experimental model of left ventricular dysfunction post-myocardial infarction. Methods: [3H]Prazosin binding was determined in arterial segments of Wistar-Kyoto rats (WKY), and of Wistar rats 5 weeks after myocardial infarction (MI) or sham operation (SHAM). Results: In the thoracic aorta (TAO) of WKY, specific prazosin binding was: (i) prevented by the irreversible α1B-AR and relatively selective α1D-AR antagonist, chloroethylclonidine (CEC); (ii) displaced with low affinity (pKi 6.25) by the α1A-AR selective ligand, (+)-niguldipine; and (iii) displaced with both high (pKi 10.4) and low (pKi 7.37) affinity by the α1D-AR antagonist, BMY 7378. In mesenteric small arteries (MSA) of WKY, prazosin binding was: (i) reduced 50% by CEC; (ii) displaced in a biphasic fashion by (+)-niguldipine (pKi 8.60 and pKi 6.22); and (iii) displaced by BMY 7378 with low affinity only (pKi 6.86). Also in TAO of SHAM, prazosin binding was prevented by CEC, but neither 30 nM (+)-niguldipine nor 1 nM BMY 7378 affected it. In MSA of SHAM, prazosin binding was virtually abolished in the presence of 30 nM (+)-niguldipine and was not reduced by 1 nM BMY 7378. In TAO and MSA of MI, compared to SHAM, the density of binding sites tended to be increased rather than decreased and neither the affinity for the ligand nor the effects of α1-AR subtype selective tools were significantly modified. Conclusions: These findings indicate that: (i) radioligand binding can be applied in intact arterial segments to quantify and characterize α1-AR; (ii) although differences seem to exist between rat strains, α1B-AR and α1D-AR predominate in rat thoracic aorta and α1A-AR and α1B-AR in mesenteric small arteries; and (iii) α1-AR density is not reduced in the poorly innervated aorta and the densely innervated mesenteric small arteries of rats with heart failure due to myocardial infarction. [ABSTRACT FROM PUBLISHER]