Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1.
Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1.
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DOI：
10.1161/circulationaha.116.026361
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发表时间：
2017-09-26
期刊：
影响因子：
37.8
通讯作者：
Brewster LP
中科院分区：
文献类型：
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作者：
Kim CW;Pokutta-Paskaleva A;Kumar S;Timmins LH;Morris AD;Kang DW;Dalal S;Chadid T;Kuo KM;Raykin J;Li H;Yanagisawa H;Gleason RL Jr;Jo H;Brewster LP
动脉僵硬度和壁剪切应力是心血管健康的重要决定因素，动脉僵硬度与心血管死亡率增加相关。低且振荡的壁剪切应力，称为扰动血流（d-flow），促进动脉粥样硬化动脉重塑，但 d-flow 与动脉僵硬度之间的关系尚不清楚。本研究的目的是确定 d-flow 对动脉硬化的作用，并发现 d-flow 使动脉硬化的相关信号通路。在年轻和年老小鼠的颈动脉中诱导 D 流。通过圆柱形双轴机械测试对动脉硬度进行离体量化，并通过双重超声对体内动脉硬度进行量化，并与来自 80 周龄小鼠的未操作的颈动脉进行比较。对富含内皮细胞的 RNA 进行基因表达和通路分析，并通过免疫组织化学进行验证。在振荡和层流壁剪切应力条件下进行信号通路的体外测试。对 d 流和稳定流 (s-flow) 区域的人类动脉进行离体测试，以验证动物模型的关键结果。部分颈动脉结扎后，D-flow 通过胶原沉积诱导动脉硬化，硬化程度与 80 周龄小鼠未操作的颈动脉相似。内膜基因通路分析发现，转化生长因子-β (TGF-β) 通路在这种动脉硬化反应中发挥着重要作用，但这是由于血小板反应蛋白-1 (TSP-1) 对促纤维化基因的刺激，而不是 TGF-β 的变化。 d-flow 条件下的体外和体内测试确定了 TSP-1 激活 TGF-β 在这些基因上调中的可能作用。与野生型颈动脉相比，TSP-1 敲除动物对 d-flow 的动脉硬化反应明显减轻。暴露于 d-flow 的人类动脉 TSP-1 和胶原蛋白基因表达也有类似的增加，如我们的模型中所见。 TSP-1 在剪切介导的动脉硬化中发挥着关键作用，这部分是通过 TSP-1 激活 TGF-β 的促纤维化信号通路介导的。该通路中的分子靶标可能会带来新的疗法，以限制动脉硬化和暴露于 d-flow 的动脉疾病的进展。
Arterial stiffness and wall shear stress are powerful determinants of cardiovascular health, and arterial stiffness is associated with increased cardiovascular mortality. Low and oscillatory wall shear stress, termed disturbed flow (d-flow), promotes atherosclerotic arterial remodeling, but the relationship between d-flow and arterial stiffness is not well understood. The objective of this study was to define the role of d-flow on arterial stiffening and discover the relevant signaling pathways by which d-flow stiffens arteries. D-flow was induced in the carotid arteries of young and old mice of both sexes. Arterial stiffness was quantified ex vivo with cylindrical biaxial mechanical testing and in vivo from duplex ultrasound and compared to unmanipulated carotid arteries from 80-week-old mice. Gene expression and pathway analysis was performed on endothelial cell-enriched RNA and validated by immunohistochemistry. In vitro testing of signaling pathways was performed under oscillatory and laminar wall shear stress conditions. Human arteries from regions of d-flow and stable flow (s-flow) were tested ex vivo to validate critical results from the animal model. D-flow induced arterial stiffening through collagen deposition after partial carotid ligation, and the degree of stiffening was similar to that of unmanipulated carotid arteries from 80-week-old mice. Intimal gene pathway analyses identified that transforming growth factor-beta (TGF-β) pathways having a prominent role in this stiffened arterial response, but that this was due to thrombospondin-1 (TSP-1) stimulation of profibrotic genes and not changes to TGF- β. In vitro and in vivo testing under d-flow conditions identified a possible role for TSP-1 activation of TGF-β in the upregulation of these genes. TSP-1 knockout animals had significantly less arterial stiffening in response to d-flow than wild type carotid arteries. Human arteries exposed to d-flow had similar increases TSP-1 and collagen gene expression as seen in our model. TSP-1 has a critical role in shear-mediated arterial stiffening that is mediated in part through TSP-1’s activation of TGF-β’s profibrotic signaling pathways. Molecular targets in this pathway may lead to novel therapies to limit arterial stiffening and the progression of disease in arteries exposed to d-flow.