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 α (TNFα) 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 TNFα stimulation resulted in the induction of COX2. The overexpression, silencing, or pharmacological inhibition of COX2 significantly affected TNFα-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, Δ¹²-PGJ₂, and 15-d-PGJ₂, strongly induced phenotypic conversion. A reporter gene assay showed that TNFα, 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 δ (PPARδ) significantly influenced 15-d-PGJ₂-induced phenotypic conversion. Finally, atherosclerotic neointima formation was significantly suppressed in mice lacking TNFα. 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.

由于慢性炎症与动脉粥样硬化的发病机制有关，因此炎性细胞因子可能有助于血管平滑肌细胞 (VSMC) 的表型调节。肿瘤坏死因子 α (TNFα) 促进了收缩性 VSMC 向合成表型的转化，这由标记蛋白的表达和胶原凝胶收缩试验确定。Western印迹分析和环氧合酶2（COX2）启动子测定显示TNFα刺激导致COX2的诱导。COX2 的过表达、沉默或药理学抑制显着影响 TNFα 诱导的表型转换，并且在测试的前列腺素中，只有 PGD ₂显着诱导表型转换。ERK 被 PGD _{2显着激活}刺激，ERK 的药理抑制阻断了 PGD ₂诱导的 VSMC 表型转化。然而，PGD ₂受体的拮抗剂或激动剂不影响VSMC转化。相反，PGD ₂的自发脱水形式，如PGJ ₂、Δ ¹² -PGJ ₂和15-d- PGJ ₂，强烈诱导表型转化。报告基因检测显示 TNFα、PGD ₂和 15-d-PGJ ₂显着激活过氧化物酶体增殖物反应元件 (PPRE) 启动子。此外，过氧化物酶体增殖物激活受体δ (PPARδ) 的过表达或沉默显着影响 15-d-PGJ_2-诱导的表型转换。最后，在缺乏 TNFα 的小鼠中，动脉粥样硬化新内膜的形成被显着抑制。此外，喂食塞来昔布的小鼠表现出完全抑制颈动脉结扎诱导的新内膜形成。这项研究表明，PGD ₂通过产生 PPAR 的内源性配体来调节 VSMC 的表型转化，这会导致闭塞性动脉疾病中的新内膜形成。