Reduced nitric oxide – cyclic guanosine monophosphate (cGMP) signaling is observed in age-related vascular disease. We hypothesize that this disturbed signaling involves effects of genomic instability, a primary causal factor in aging, on vascular smooth muscle cells, 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 (Ercc1d/- mice), human VSMC cultures and population GWAs studies. Aortic rings of Ercc1d/- showed 43% reduced responses to the soluble guanylyl cyclase (sGC) stimulator sodium nitroprusside (SNP). Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNPrelaxing 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/- . No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1d/- mice vs. WT. Senescent human VSMC showed elevated PDE1A and PDE1C and PDE5 mRNA levels (by 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 (β= 0.28, p= 2.47x10-5) and carotid intima media thickness (β= -0.0061, p= 2.89x10-5). In summary, these results show that genomic instability and cellular senescence in VSMC increase PDE1 expression. This might play a role in to aging-related loss of vasodilator function, VSMC senescence, increased blood pressure and vascular hypertrophy.
- Copyright 2015 The Author(s)
Archiving permitted only in line with the archiving policy of Portland Press Limited. All other rights reserved.