Placental Growth Factor Levels in Quadriceps Muscle Are Reduced by a Western Diet in Association With Advanced Glycation End Products.
Placental Growth Factor Levels in Quadriceps Muscle Are Reduced by a Western Diet in Association With Advanced Glycation End Products.
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DOI：
10.1152/ajpheart.00511.2018
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发表时间：
2019-10
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影响因子：
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通讯作者：
Asitha T. Silva;F. Rouf;Oluwayemisi A. Semola;M. Payton;Pamela C. Lovern
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文献类型：
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作者：
Asitha T. Silva;F. Rouf;Oluwayemisi A. Semola;M. Payton;Pamela C. Lovern
外周动脉疾病（PAD），动脉粥样硬化闭塞慢性损害肢体血流。动脉生成（侧支动脉重塑）是对PAD的重要适应性反应，可保护组织免受缺血。II型糖尿病患者患PAD的风险很高，可以从动脉生成中获益。然而，糖尿病患者的动脉生成受到多方面机制的抑制，这一机制尚未完全确定。胎盘生长因子（PLGF）的上调是动脉形成的关键早期步骤。因此，我们假设代谢功能障碍会损害骨骼肌中PLGF的表达。我们在喂食西方饮食（WD） 24周的C57BL/6J和ApoE-/-小鼠中验证了这一假设。我们首先评估了后肢骨骼肌中PLGF、血管内皮生长因子（VEGF- a）和VEGF受体1 （VEGFR-1）蛋白的基线水平。只有PLGF随WD持续下降。接下来，我们研究了24周WD对PLGF、VEGF-A、VEGFR1和单核细胞趋化蛋白-1 （MCP-1）对血管闭塞生理刺激的反应的影响。用ameroid缩窄器渐进式阻断股动脉诱导小鼠后肢缺血。术后3-28 d测量生长因子水平。在C57BL/6J小鼠中，WD可降低和延迟PLGF的上调，消除VEGF-A和VEGFR-1的上调，但对MCP-1无影响。在饲喂任何一种饮食的ApoE-/-小鼠中，所有测试的因素对阻断均无反应。小鼠代谢表型和体外研究表明，晚期糖基化终产物(AGE)/ tnf α介导的机制可能有助于体内观察到的效果。
In peripheral artery disease (PAD), atherosclerotic occlusion chronically impairs limb blood flow. Arteriogenesis (collateral artery remodeling) is a vital adaptive response to PAD that protects tissue from ischemia. Type II diabetics have a high risk of developing PAD, and would benefit from arteriogenesis. However, arteriogenesis is suppressed in diabetics by a multifaceted mechanism which remains incompletely defined. Upregulation of placental growth factor (PLGF) is a key early step in arteriogenesis. Therefore, we hypothesized that metabolic dysfunction would impair PLGF expression in skeletal muscle. We tested this hypothesis in C57BL/6J and ApoE-/- mice of both sexes fed a Western diet (WD) for 24 wk. We first assessed baseline levels of PLGF, vascular endothelial growth factor (VEGF-A), and VEGF receptor 1 (VEGFR-1) protein in hindlimb skeletal muscle. Only PLGF was consistently decreased by the WD. We next investigated the effect of 24 wk of the WD on the response of PLGF, VEGF-A, VEGFR1, and monocyte chemoattractant protein-1 (MCP-1) to the physiological stimulus of vascular occlusion. Hindlimb ischemia was induced in mice by gradual femoral artery occlusion using an ameroid constrictor. Growth factor levels were measured 3-28 d post-surgery. In C57BL/6J mice, the WD decreased and delayed upregulation of PLGF, and abolished upregulation of VEGF-A and VEGFR-1, but had no effect on MCP-1. In ApoE-/- mice fed either diet, all factors tested failed to respond to occlusion. Metabolic phenotyping of mice and in vitro studies suggest that an advanced glycation end product (AGE)/TNFα-mediated mechanism could contribute to the effects observed in vivo.