Abstract
The objective of this study is to explore the role of the SDF-1α/CXCR4 pathway in the development of intracranial aneurysm (IA) induced by hemodynamic forces. We collected 12 IA and six superficial temporal artery samples for high-throughput sequencing, hematoxylin and eosin staining, and immunohistochemistry to examine vascular remodeling and determine the expression of the components of the SDF-1α/CXCR4 pathway, structural proteins (α-SMA and calponin) of vascular smooth muscle cells (VSMCs), and inflammatory factors (MMP-2 and TNF-α). Computational fluid dynamics (CFD) was used for hemodynamic analysis. Mouse IA model and dynamic co-culture model were established to explore the mechanism through which the SDF-1α/CXCR4 pathway regulates the phenotypic transformation of VSMCs in vivo and in vitro. We detected a significant elevation of SDF-1α and CXCR4 in IA, which was accompanied by vascular remodeling in the aneurysm wall (i.e., the upregulation of inflammatory factors, MMP-2 and TNF-α, and the downregulation of contractile markers, α-SMA and calponin). In addition, hemodynamic analysis revealed that compared with unruptured aneurysms, ruptured aneurysms were associated with lower wall shear stress and higher MMP-2 expression. In vivo and in vitro experiments showed that abnormal hemodynamics could activate the SDF-1α/CXCR4, P38, and JNK signaling pathways to induce the phenotypic transformation of VSMCs, leading to IA formation. Hemodynamics can induce the phenotypic transformation of VSMCs and cause IA by activating the SDF-1α/CXCR4 signaling pathway.
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The study was supported by the National Key R&D Program of China (2016YFC1300700) and Natural Science Foundation of China (no. 81771264).
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Y.Z.Y. and Q.H.H. contributed to project conception and design and provided financial support. Y.Z.Y., J.C.X., F.F.X., C.C.W, Z.W.Z., H.S.T., and Z.W.L conducted the experiment. Y.Z.Y., J.C.X., and F.F.X. participated in the collection of data, analyzed and interpreted data, and wrote the manuscript. Q.H.H. critically revised the article and approved the final version of the manuscript on behalf of all the authors. Y.Z.Y., J.C.X., and F.F.X. contributed equally to this work.
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12975_2021_925_MOESM1_ESM.jpg
Supplementary file1. Determination of the most appropriate wall shear stress (WSS) stimulation and drug concentration. (A) In vitro co-culture schematic. Human umbilical venous endothelial cells (HUVECs) were plated on the bottom surface of the transwell membrane. After 2 h of culture, human brain vascular smooth muscle cells (HBVSMCs) were plated on the inner surface of the membrane. After 24 h of culture, the cells were dynamically cultured in the Flow Chamber. (B-E) Different WSS were applied to this co-culture model to identify the most suitable WSS application. The highest expression of SDF-1α, CXCR4, and MMP-2 was observed at12 dyn/cm2 WSS, and the expression of α-SMA was significantly lower than that of static culture. Therefore, WSS 12 dyn/cm2 was used for 12 h intervention. (F-I) Different concentrations of AMD3100 and SDF-1α were applied to the co-culture model to identify the most suitable drug concentration. At 12 dyn/cm2 WSS for 12 h, the highest expression of α-SMA was observed with 10 μM AMD3100, while the expression of MMP-2 was significantly inhibited. At 100 ng/ml SDF-1α, the expression of α-SMA was significantly inhibited, whereas the highest expression level of MMP-2 was observed at this concentration. Therefore, 10 μM AMD3100 and 100 ng/ml recombinant human SDF-1α were used for follow-up intervention. Each experiment was performed at least three times. * p < 0.05; ** p < 0.01; *** p < 0.001. (JPG 651 KB)
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Yan, Y., Xiong, J., Xu, F. et al. SDF-1α/CXCR4 Pathway Mediates Hemodynamics-Induced Formation of Intracranial Aneurysm by Modulating the Phenotypic Transformation of Vascular Smooth Muscle Cells. Transl. Stroke Res. 13, 276–286 (2022). https://doi.org/10.1007/s12975-021-00925-1
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DOI: https://doi.org/10.1007/s12975-021-00925-1