Prostaglandin D₂ stimulates phenotypic changes in vascular smooth muscle cells.

ABSTRACT: Since chronic inflammation is associated with the pathogenesis of atherosclerosis, inflammatory cytokines might contribute to the phenotypic modulation of vascular smooth muscle cells (VSMCs). Tumor necrosis factor ? (TNF?) facilitated the transformation of contractile VSMCs to the synthetic phenotype, as determined by the expression of marker proteins and a collagen gel contraction assay. Western blot analysis and a cyclooxygenase-2 (COX2) promoter assay revealed that TNF? stimulation resulted in the induction of COX2. The overexpression, silencing, or pharmacological inhibition of COX2 significantly affected TNF?-induced phenotypic conversion, and of the tested prostaglandins, only PGD₂ significantly induced phenotypic conversion. ERK was significantly activated by PGD₂ stimulation, and the pharmacological inhibition of ERK blocked the PGD₂-induced phenotypic conversion of VSMCs. However, antagonists or agonists of PGD₂ receptors did not affect VSMC conversion. In contrast, spontaneously dehydrated forms of PGD₂, such as PGJ₂, ?¹²-PGJ₂, and 15-d-PGJ₂, strongly induced phenotypic conversion. A reporter gene assay showed that TNF?, PGD₂, and 15-d-PGJ₂ significantly activated the peroxisome proliferator-responsive element (PPRE) promoter. In addition, the overexpression or silencing of peroxisome proliferator-activated receptor ? (PPAR?) significantly influenced 15-d-PGJ₂-induced phenotypic conversion. Finally, atherosclerotic neointima formation was significantly suppressed in mice lacking TNF?. In addition, mice fed celecoxib exhibited complete inhibition of carotid artery ligation-induced neointima formation. This study shows that PGD₂ regulates the phenotypic conversion of VSMCs by generating an endogenous ligand of PPAR, and that this leads to neointima formation in occlusive arterial disease.

SUBMITTER: Lee HS 

PROVIDER: S-EPMC6859158 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature