Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice.
Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice.
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DOI：
10.1098/rsif.2021.0336
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Humphrey JD
中科院分区：
文献类型：
--
作者：
Spronck B;Latorre M;Wang M;Mehta S;Caulk AW;Ren P;Ramachandra AB;Murtada SI;Rojas A;He CS;Jiang B;Bersi MR;Tellides G;Humphrey JD
高血压引起显著的主动脉重构，通常是适应性的，但有时不是。为了确定差异性重塑的免疫机械机制，我们研究了129 S6/SvEvTac和C57 BL/6 J小鼠在连续14天血管紧张素II输注前后的胸部动脉瘤，这两种品系的血压升高相似。切除血管的组织学和生物力学评估在基线时相似，表明平均血管壁应力的稳态设定点相同。组织学进一步揭示了高血压129 S6/SvEvTac椎间盘的近机械适应性重塑，但C57 BL/6 J椎间盘的严重适应性重塑。批量RNA测序表明，平滑肌收缩过程的增加促进了129 S6/SvEvTac肌细胞的机械适应，而免疫过程阻止了C57 BL/6 J肌细胞的适应。功能研究证实前者的血管收缩能力增加，而免疫组织化学显示后者的炎性细胞显著增加。然后，我们使用多种计算生物力学模型来检验过度的外膜壁应力与炎性细胞浸润相关的假设。这些模型一致地预测，增加的血管收缩对抗增加的压力，加上适度沉积的新基质适当地增厚壁，恢复壁应力朝向与适应性重塑一致的稳态。相比之下，血管收缩不足允许高壁应力和旺盛的炎症驱动的基质沉积，特别是在外膜中，反映了稳态受损和总体适应不良。
Hypertension induces significant aortic remodeling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodeling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodeling of the hypertensive 129S6/SvEvTac aortas, but grossly maladaptive remodeling of C57BL/6J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress toward homeostatic consistent with adaptive remodeling. In contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.
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影响因子：
20.1
作者：
Bardy, N;Merval, R;Tedgui, A
通讯作者：
Tedgui, A
影响因子：
2.1
作者：
BROWNLEE, RD;LANGILLE, BL
通讯作者：
LANGILLE, BL
影响因子：
8.3
作者：
Lerman, Lilach O.;Kurtz, Theodore W.;Coffman, Thomas M.
通讯作者：
Coffman, Thomas M.
DOI：
10.1152/ajpheart.01047.2006
发表时间：
2007-03-01
影响因子：
4.8
作者：
Chien, Shu
通讯作者：
Chien, Shu
影响因子：
4.8
作者：
Kozel, Beth A.;Knutsen, Russell H.;Mecham, Robert P.
通讯作者：
Mecham, Robert P.