PDF(Pubmed)
Abstract：
The intima, comprising the endothelium and the subendothelial matrix, plays a crucial role in atherosclerosis pathogenesis. The mechanical stress arising from disturbed blood flow (d-flow) and the stiffening of the arterial wall contributes to endothelial dysfunction. However, the specific impacts of these physical forces on the mechanical environment of the intima remain undetermined. Here, we investigated whether inhibiting collagen crosslinking could ameliorate the detrimental effects of persistent d-flow on the mechanical properties of the intima. Partial ligation of the left carotid artery (LCA) was performed in C57BL/6J mice, inducing d-flow. The right carotid artery (RCA) served as an internal control. Carotids were collected 2 days and 2 weeks after surgery to study acute and chronic effects of d-flow on the mechanical phenotype of the intima. The chronic effects of d-flow were decoupled from the ensuing arterial wall stiffening by administration of β-aminopropionitrile (BAPN), an inhibitor of collagen crosslinking by lysyl oxidase (LOX) enzymes. Atomic force microscopy (AFM) was used to determine stiffness of the endothelium and the denuded subendothelial matrix in en face carotid preparations. The stiffness of human aortic endothelial cells (HAEC) cultured on soft and stiff hydrogels was also determined. Acute exposure to d-flow caused a slight decrease in endothelial stiffness in male mice but had no effect on the stiffness of the subendothelial matrix in either sex. Regardless of sex, the intact endothelium was softer than the subendothelial matrix. In contrast, exposure to chronic d-flow led to a substantial increase in the endothelial and subendothelial stiffness in both sexes. The effects of chronic d-flow were largely prevented by concurrent BAPN administration. In addition, HAEC displayed reduced stiffness when cultured on soft vs. stiff hydrogels. We conclude that chronic d-flow results in marked stiffening of the arterial intima, which can be effectively prevented by inhibition of collagen crosslinking.
摘要：
内膜，包括内皮和内皮下基质，在动脉粥样硬化的发病机制中起着至关重要的作用。血流（d流）紊乱和动脉壁变硬引起的机械应力会导致内皮功能障碍。然而,这些物理力对内膜机械环境的具体影响仍不确定。这里,我们研究了抑制胶原交联是否可以改善持续d流对内膜机械性能的不利影响。在C57BL/6J小鼠中进行左颈动脉（LCA）的部分结扎，诱导d流。右颈动脉(RCA)作为内部对照。手术后2天和2周收集颈动脉，以研究d流对内膜机械表型的急性和慢性影响。通过施用β-氨基丙腈（BAPN），d流的慢性作用与随后的动脉壁硬化无关，通过赖氨酰氧化酶（LOX）酶的胶原交联的抑制剂。原子力显微镜（AFM）用于确定面部颈动脉制剂中内皮和内皮下基质的硬度。还确定了在柔软和坚硬的水凝胶上培养的人主动脉内皮细胞（HAEC）的硬度。急性暴露于d流导致雄性小鼠的内皮硬度略有降低，但对两种性别的内皮下基质的硬度均无影响。不管性别,完整的内皮比内皮下基质软。相比之下,暴露于慢性d流导致两种性别的内皮和内皮下僵硬度大幅增加。同时施用BAPN在很大程度上防止了慢性d流的影响。此外,HAEC在柔软与柔软上培养时显示出降低的刚度硬水凝胶。我们得出的结论是，慢性d流导致动脉内膜明显变硬，可以通过抑制胶原交联来有效地防止。
