Department of Physiological Sciences, Oklahoma State University, Stillwater, Oklahoma.
Department of Mechanical and Aerospace Engineering, Oklahoma State University, Stillwater, Oklahoma.
Am J Physiol Heart Circ Physiol. 2019 Oct 1;317(4):H851-H866. doi: 10.1152/ajpheart.00511.2018. Epub 2019 Aug 9.
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. People with type II diabetes have a high risk of developing PAD and would benefit from arteriogenesis. However, arteriogenesis is suppressed in people with diabetes 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 (VEGFR1) 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 days postsurgery. In C57BL/6J mice, the WD decreased and delayed upregulation of PLGF and abolished upregulation of VEGF-A and VEGFR1 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/TNFα-mediated mechanism could contribute to the effects observed in vivo. In this study, we tested the effect of a Western diet on expression of the arteriogenic growth factor placental growth factor (PLGF) in mouse skeletal muscle. We provide the first demonstration that a Western diet interferes with both baseline expression and hindlimb ischemia-induced upregulation of PLGF. We further identify a potential role for advanced glycation end product/TNFα signaling as a negative regulator of PLGF. These studies provide insight into one possible mechanism by which type II diabetes may limit collateral growth.
在周围动脉疾病（PAD）中，动脉粥样硬化阻塞会导致肢体血液流动长期受损。动脉生成（侧支动脉重塑）是一种对 PAD 的重要适应性反应，可以保护组织免受缺血的影响。患有 2 型糖尿病的人患 PAD 的风险很高，并且可以从动脉生成中受益。然而，糖尿病患者的动脉生成受到多种机制的抑制，这些机制仍不完全明确。胎盘生长因子（PLGF）的上调是动脉生成的关键早期步骤。因此，我们假设代谢功能障碍会损害骨骼肌中的 PLGF 表达。我们在 C57BL/6J 和 ApoE 雄性和雌性小鼠中测试了这一假设，这些小鼠在喂食西方饮食（WD）24 周后。我们首先评估了后肢骨骼肌中 PLGF、血管内皮生长因子（VEGF-A）和血管内皮生长因子受体 1（VEGFR1）蛋白的基线水平。只有 PLGF 被 WD 持续降低。接下来，我们研究了 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反应的影响。通过使用 ameroid 缩窄器逐渐阻塞股动脉，在小鼠中诱导后肢缺血。手术后 3-28 天测量生长因子水平。在 C57BL/6J 小鼠中，WD 降低并延迟了 PLGF 的上调，并消除了 VEGF-A 和 VEGFR1 的上调，但对 MCP-1 没有影响。在喂食两种饮食的 ApoE 小鼠中，所有测试的因素都未能对闭塞作出反应。对小鼠的代谢表型和体外研究表明，晚期糖基化终产物/TNFα介导的机制可能导致体内观察到的影响。在这项研究中，我们测试了西方饮食对小鼠骨骼肌中成血管生长因子胎盘生长因子（PLGF）表达的影响。我们首次证明，西方饮食会干扰 PLGF 的基础表达和后肢缺血诱导的上调。我们进一步确定晚期糖基化终产物/TNFα信号作为 PLGF 的负调节剂的潜在作用。这些研究为 2 型糖尿病可能限制侧支生长的一种可能机制提供了深入了解。
