Department of Mechanical Engineering, Koç University, Istanbul, Turkey.
Department of Histology & Embryology, School of Medicine, Koç University, Istanbul, Turkey.
Am J Physiol Heart Circ Physiol. 2020 May 1;318(5):H1208-H1218. doi: 10.1152/ajpheart.00495.2019. Epub 2020 Apr 3.
In the embryonic heart, blood flow is distributed through a bilaterally paired artery system composed of the aortic arches (AAs). The purpose of this study is to establish an understanding of the governing mechanism of microstructural maturation of the AA matrix and its reversibility, toward the desired macroscopic vessel lumen diameter and thickness for healthy, abnormal, and in ovo repaired abnormal mechanical loading. While matrix-remodeling mechanisms were significantly different for normal versus conotruncal banding (CTB), both led to an increase in vessel lumen. Correlated with right-sided flow increase at Hamburger & Hamilton stages 21, intermittent load switching between collagen I and III with elastin and collagen-IV defines the normal process. However, decreases in collagen I, elastin, vascular endothelial growth factor-A, and fibrillin-1 in CTB were recovered almost fully following the CTB-release model, primarily because of the pressure load changes. The complex temporal changes in matrix proteins are illustrated through a predictive finite-element model based on elastin and collagen load-sharing mechanism to achieve lumen area increase and thickness increase resulting from wall shear stress and tissue strain, respectively. The effect of embryonic timing in cardiac interventions on AA microstructure was established where abnormal mechanical loading was selectively restored at the key stage of development. Recovery of the normal mechanical loading via early fetal intervention resulted in delayed microstructural maturation. Temporal elastin increase, correlated with wall shear stress, is required for continuous lumen area growth. The present study undertakes comparative analyses of the mechanistic differences of the arterial matrix microstructure and dynamics in the three fundamental processes of control, conotruncal banded, and released conotruncal band in avian embryo. Among other findings, this study provides specific evidence on the restorative role of elastin during the early lumen growth process. During vascular development, a novel intermittent load-switching mechanism between elastin and collagen, triggered by a step increase in wall shear stress, governs the chronic vessel lumen cross-sectional area increase. Mimicking the fetal cardiovascular interventions currently performed in humans, the early release of the abnormal mechanical load rescues the arterial microstructure with time lag.
在胚胎心脏中，血流通过由主动脉弓（AA）组成的双侧配对动脉系统分布。本研究旨在建立对 AA 基质微观结构成熟的控制机制及其可恢复性的理解，以实现健康、异常和胚胎修复异常机械负荷的理想宏观血管腔直径和厚度。虽然正常与圆锥动脉干带（CTB）的基质重塑机制有显著差异，但两者都导致了血管腔的增加。与 Hamburger & Hamilton 阶段 21 的右侧血流增加相关，胶原蛋白 I 和 III 与弹性蛋白和胶原蛋白-IV 之间的间歇性负荷转换定义了正常过程。然而，CTB 释放模型后，CTB 中的胶原蛋白 I、弹性蛋白、血管内皮生长因子-A 和原纤维蛋白-1 几乎完全恢复，主要是由于压力负荷变化。通过基于弹性蛋白和胶原蛋白载荷分担机制的预测有限元模型，阐明了基质蛋白的复杂时间变化，以实现由于壁面切应力和组织应变分别导致的腔面积增加和厚度增加。通过胚胎心脏干预对 AA 微观结构的时间影响建立了模型，其中异常机械负荷在发育的关键阶段被选择性恢复。通过早期胎儿干预恢复正常机械负荷导致微观结构成熟延迟。与壁面切应力相关的弹性蛋白的时间增加是连续腔面积生长所必需的。本研究对鸟类胚胎中控制、圆锥动脉干带和释放的圆锥动脉干三个基本过程中动脉基质微观结构和动力学的机制差异进行了比较分析。除其他发现外，本研究还提供了关于弹性蛋白在早期管腔生长过程中恢复作用的具体证据。在血管发育过程中，壁面切应力的阶跃增加触发了弹性蛋白和胶原蛋白之间的新型间歇性负荷转换机制，控制着慢性血管腔横截面积的增加。模拟目前在人类中进行的胎儿心血管干预，早期释放异常机械负荷会随着时间的推移挽救动脉微观结构。
