VSMCs (vascular smooth muscle cells) play critical roles in arterial remodelling with aging,
hypertension and
atherosclerosis. VSMCs exist in diverse phenotypes and exhibit phenotypic plasticity, e.g. changing from a quiescent/contractile phenotype to an active myofibroblast-like, often called 'synthetic', phenotype. Synthetic VSMCs are able to proliferate, migrate and secrete ECM (extracellular matrix)
proteinases and ECM
proteins. In addition, they produce pro-inflammatory molecules, providing an inflammatory microenvironment for leucocyte penetration, accumulation and activation. The aging VSMCs have also shown changes in cellular phenotype, responsiveness to contracting and relaxing mediators, replicating potential, matrix synthesis, inflammatory mediators and intracellular signalling. VSMC dysfunction plays a key role in age-associated vascular remodelling.
Cyclic nucleotide PDEs (
phosphodiesterases), by catalysing
cyclic nucleotide hydrolysis, play a critical role in regulating the amplitude, duration and compartmentalization of
cyclic nucleotide signalling. Abnormal alterations of
PDEs and subsequent changes in
cyclic nucleotide homoeostasis have been implicated in a number of different diseases. In the study published in the latest issue of Clinical Science, Bautista Niño and colleagues have shown that, in cultured senescent human VSMCs, PDE1A and PDE1C
mRNA levels are significantly up-regulated and inhibition of PDE1 activity with
vinpocetine reduced cellular senescent makers in senescent VSMCs. Moreover, in the
premature aging mice with
genomic instability (Ercc1(d/-)), impaired aortic ring relaxation in response to SNP (
sodium nitroprusside), an NO (
nitric oxide) donor, was also largely improved by
vinpocetine. More interestingly, using data from human GWAS (genome-wide association studies), it has been found that PDE1A single nucleotide polymorphisms is significantly associated with diastolic blood pressure and carotid intima-media thickening, two hallmarks of human vascular dysfunction in aging. These findings establish a strong relationship between PDE1 expression regulation and vascular abnormalities in aging.