Intracellular signaling control of mechanical homeostasis in the aorta.
Intracellular signaling control of mechanical homeostasis in the aorta.
复制标题
主动脉中机械稳态的细胞内信号控制。
DOI：
10.1007/s10237-022-01593-2
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发表时间：
2022-10
影响因子：
3.5
通讯作者：
Humphrey, Jay D.
中科院分区：
文献类型：
--
作者：
Irons, Linda;Estrada, Ana C.;Humphrey, Jay D.
成熟动脉在健康状态下表现出较好的生物力学状态，其证据是壁内和壁面剪应力的范围较窄。当压力受到血压或血流变化的干扰时，稳态机制往往通过改变收缩性和/或细胞和基质周转来恢复目标值。相比之下，血管疾病与受损的内稳态有关，因此我们必须了解机械内稳态及其鲁棒性的机制。在这里，我们使用一个多尺度的计算模型，其中机械敏感的细胞内信号通路驱动动脉生长和重塑。首先，我们确定了一个合奏的细胞水平的参数化，组织水平的反应得到很好的调节和适应血流动力学扰动。负责的机制是持续的多尺度负反馈，从而机械敏感信号驱动质量周转，直到达到稳态目标应力。这证明了尽管不可避免的细胞和个体异质性，但稳健性是如何出现的。其次，我们研究了信号节点敲除（ATIR，ROCK，TGFβRII，PDGFR，ERK 1/2）的组织水平效应，并发现与容错的实验报告基本一致。对结构变化的鲁棒性通过基线应力下节点的低参与或通过额外途径的上调的补偿性多尺度反馈来体现。第三，我们展示了敲低如何影响胶原蛋白和平滑肌在基线和扰动应力下的周转。在一些情况下，基础生产没有受到显着影响，但应力偏差的敏感性，影响反馈强度，降低。这种减少可能会损害适应性反应，与以前报道的主动脉脆弱性一致，尽管外观大体正常。因此，降低的压力敏感性形成了一个候选机制，说明健壮性是如何丧失的，从而使从健康向疾病过渡。
Mature arteries exhibit a preferred biomechanical state in health evidenced by a narrow range of intramural and wall shear stresses. When stresses are perturbed by changes in blood pressure or flow, homeostatic mechanisms tend to restore target values via altered contractility and/or cell and matrix turnover. In contrast, vascular disease associates with compromised homeostasis, hence we must understand mechanisms underlying mechanical homeostasis and its robustness. Here, we use a multiscale computational model wherein mechanosensitive intracellular signaling pathways drive arterial growth and remodeling. First, we identify an ensemble of cell-level parameterizations where tissue-level responses are well-regulated and adaptive to hemodynamic perturbations. The responsible mechanism is persistent multiscale negative feedback whereby mechanosensitive signaling drives mass turnover until homeostatic target stresses are reached. This demonstrates how robustness emerges despite inevitable cell and individual heterogeneity. Second, we investigate tissue-level effects of signaling node knockdowns (ATIR, ROCK, TGFβRII, PDGFR, ERK1/2) and find general agreement with experimental reports of fault tolerance. Robustness against structural changes manifests via low engagement of the node under baseline stresses or compensatory multiscale feedback via upregulation of additional pathways. Third, we show how knockdowns affect collagen and smooth muscle turnover at baseline and with perturbed stresses. In several cases, basal production is not remarkably affected, but sensitivities to stress deviations, which influence feedback strength, are reduced. Such reductions can impair adaptive responses, consistent with previously reported aortic vulnerability despite grossly normal appearances. Reduced stress sensitivities thus form a candidate mechanism for how robustness is lost, enabling transitions from health towards disease.
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影响因子：
3.8
作者：
Irons L;Latorre M;Humphrey JD
通讯作者：
Humphrey JD
DOI：
10.1126/science.1192149
发表时间：
2011-04-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Holm TM;Habashi JP;Doyle JJ;Bedja D;Chen Y;van Erp C;Lindsay ME;Kim D;Schoenhoff F;Cohn RD;Loeys BL;Thomas CJ;Patnaik S;Marugan JJ;Judge DP;Dietz HC
通讯作者：
Dietz HC
影响因子：
3.9
作者：
Bellini, C.;Bersi, M. R.;Humphrey, J. D.
通讯作者：
Humphrey, J. D.
影响因子：
4.3
作者：
Irons, Linda;Humphrey, Jay D.
通讯作者：
Humphrey, Jay D.
影响因子：
--
作者：
Kraeutler, Matthew J.;Soltis, Anthony R.;Saucerman, Jeffrey J.
通讯作者：
Saucerman, Jeffrey J.