Endothelial dysfunction promotes age-related reorganization of collagen fibers and alters aortic biomechanics in mice.

IF 4.1 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Liya Du, Jeffrey Rodgers, Nazli Gharraee, Olivia Gary, Tarek Shazly, John F Eberth, Susan M Lessner
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Abstract

Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide (NO), is a risk factor for the occurrence and progression of various vascular diseases. This study investigates the effect of endothelial dysfunction on age-related changes in aortic extracellular matrix (ECM) microstructure and the relationship between microstructural adaptation and the mechanical response. Here, we used groups of NOS3 knockout (KO), NOS3 heterozygotes (Het), and wild-type (WT) B6 mice (controls) to study changes in hemodynamic parameters, collagen fiber organization, and both active and passive aortic mechanics using biaxial pressure myography over a time course from 1.5 to 12 mo. Our results show that homeostatic levels of passive circumferential stress and stretch were preserved in KO mice by remodeling adventitial collagen fibers toward a more predominantly circumferential direction with age, rather than by increased fibrosis, in response to hypertension induced by endothelial dysfunction. However, passive aortic stiffness in KO mice was significantly increased owing to geometrical changes, including significant increases in wall thickness and decreases in inner diameter, and by ECM microstructural reorganization, during this maladaptive vascular remodeling. Furthermore, long-term NO deficiency significantly increased smooth muscle cell (SMC) contractility initially, but this effect was attenuated with age. These findings improve our understanding of microstructural and mechanical changes during the maladaptive vascular remodeling process, demonstrating a role for adventitial collagen fiber reorientation in the response to hypertension.NEW & NOTEWORTHY Endothelial dysfunction facilitates the reorganization of collagen fibers toward a more predominantly circumferential orientation with age, consequently promoting homeostatic normalization of passive circumferential stress and stretch in the vessel subjected to hypertension.

内皮功能障碍促进年龄相关的胶原纤维重组和改变小鼠主动脉生物力学。
内皮功能障碍被定义为一氧化氮(NO)生物利用度的降低,是各种血管疾病发生和发展的危险因素。本研究探讨内皮功能障碍对年龄相关性主动脉细胞外基质(ECM)微结构变化的影响,以及微结构适应与力学反应的关系。在这里,我们使用NOS3敲除(KO)、NOS3杂合子(Het)和野生型(WT) B6小鼠(对照),研究血液动力学参数、胶原纤维组织和主动和被动主动脉力学的变化,使用双轴压力肌图,时间为1.5至12个月。我们的研究结果表明,在内皮功能障碍诱导的高血压下,随着年龄的增长,通过向更主要的周向重塑外膜胶原纤维,而不是通过纤维化增加,可以保持KO小鼠被动周向应力和拉伸的稳态水平。然而,在这种不适应的血管重塑过程中,由于几何变化,包括壁厚显著增加和内径减少,以及ECM微结构重组,KO小鼠的被动主动脉僵硬度显著增加。此外,长期NO缺乏最初会显著增加平滑肌细胞(SMC)的收缩力,但这种作用随着年龄的增长而减弱。这些发现提高了我们对血管重构过程中微结构和力学变化的理解,证明了外膜胶原纤维重定向在高血压反应中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.60
自引率
10.40%
发文量
202
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology-Heart and Circulatory Physiology publishes original investigations, reviews and perspectives on the physiology of the heart, vasculature, and lymphatics. These articles include experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the intact and integrative animal and organ function to the cellular, subcellular, and molecular levels. The journal embraces new descriptions of these functions and their control systems, as well as their basis in biochemistry, biophysics, genetics, and cell biology. Preference is given to research that provides significant new mechanistic physiological insights that determine the performance of the normal and abnormal heart and circulation.
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