Vascular smooth muscle cells (VSMCs) play critical roles in arterial remodeling 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 VSMC cells are able to proliferate, migrate, and secrete extracellular matrix (ECM) proteinases and ECM proteins. In addition, they produce pro-inflammatory molecules, providing an inflammatory microenvironment for leukocyte 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 signaling. VSMC dysfunction plays a key role in age-associated vascular remodeling. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing cyclic nucleotide hydrolysis, play a critical role in regulating the amplitude, duration, and compartmentalization of cyclic nucleotide signaling. Abnormal alterations of PDEs and subsequent changes of cyclic nucleotide homeostasis have been implicated in a number of different diseases. In the study published in this issue, Nino et al have shown that in cultured senescent human VSMCs, PDE1A and PDE1C mRNA levels are sognificanly 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 (Ercc1d/-), impaired aortic ring relaxation in response to sodium nitroprusside (SNP, a NO donor) was also largely improved by vinpocetine. More interestingly, using data from human Genome-Wide Association Studies (GWAS), it has been found that PDE1A single nucleotide polymorphisms (SNP) 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.
- Copyright 2015 The Author(s)
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