Pompili V J, Gordon D, San H, Yang Z, Muller D W, Nabel G J, Nabel E G
Department of Internal Medicine, Howard Hughes Medical Institute, University of Michigan, Ann Arbor 48109-0644, USA.
Arterioscler Thromb Vasc Biol. 1995 Dec;15(12):2254-64. doi: 10.1161/01.atv.15.12.2254.
Platelet-derived growth factor (PDGF) B is a mitogen and chemoattractant for smooth muscle cells in vitro, and expression of a recombinant PDGF B gene in porcine arteries stimulates intimal thickening. To define the mechanisms by which PDGF B gene expression induces intimal thickening in vivo, we examined its effects on smooth muscle cell proliferation and migration, extracellular matrix synthesis, and inflammatory cell infiltration in intimal lesions of pig arteries after direct gene transfer of a recombinant PDGF B gene. PDGF B gene expression was associated with rapid formation of an intima, including 3- to 10-fold increases in intimal thickness and intima-to-media area ratio 4 to 21 days after gene transfer compared with control transfected arteries. Intimal smooth muscle cell proliferation was detected at 2 days, peaked at 7 days (P < .01), and declined by 14 days, although the total number of intimal nuclei progressively increased to 21 days (P < .01). Calculations of expected-to-observed ratios of intimal cells, based on BrdC proliferation indexes, demonstrated that the increases in intimal cell number on days 2 through 7 could not be accounted for by proliferation alone, suggesting that recombinant PDGF BB acts to stimulate cell proliferation and migration of smooth muscle cells into the intima. Extracellular matrix deposition and procollagen synthesis were observed after 7 days (P < .01) and were associated with a decline in cell density in the intima, suggesting that extracellular matrix synthesis may contribute to progressive intimal thickening in response to PDGF B gene expression. There was minimal accumulation of inflammatory cells, including macrophages and CD3(+) lymphocytes, in transfected arteries. These data suggest that PDGF B gene expression promotes intimal expansion by both proliferation and migration of smooth muscle cells followed by synthesis of extracellular matrix and therefore acts through several mechanisms to play a role in the pathogenesis of intimal lesions in vivo.
血小板衍生生长因子（PDGF）B在体外是平滑肌细胞的促有丝分裂剂和趋化因子，重组PDGF B基因在猪动脉中的表达会刺激内膜增厚。为了确定PDGF B基因表达在体内诱导内膜增厚的机制，我们在直接基因转移重组PDGF B基因后，研究了其对猪动脉内膜病变中平滑肌细胞增殖和迁移、细胞外基质合成以及炎性细胞浸润的影响。与对照转染动脉相比，PDGF B基因表达与内膜的快速形成相关，包括基因转移后4至21天内膜厚度和内膜与中膜面积比增加3至10倍。内膜平滑肌细胞增殖在第2天被检测到，在第7天达到峰值（P <.01），并在第14天下降，尽管内膜细胞核总数逐渐增加至第21天（P <.01）。基于BrdC增殖指数计算内膜细胞的预期与观察比率，结果表明第2天至第7天内膜细胞数量的增加不能仅由增殖来解释，这表明重组PDGF BB可刺激平滑肌细胞增殖并迁移至内膜。7天后观察到细胞外基质沉积和前胶原合成（P <.01），并且与内膜中细胞密度的下降相关，这表明细胞外基质合成可能有助于响应PDGF B基因表达而导致的内膜逐渐增厚。在转染动脉中，包括巨噬细胞和CD3(+)淋巴细胞在内的炎性细胞积累极少。这些数据表明，PDGF B基因表达通过平滑肌细胞的增殖和迁移，随后合成细胞外基质来促进内膜扩张，因此通过多种机制在体内内膜病变的发病机制中发挥作用。
