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. 2022 Apr;13(2):276-286.
doi: 10.1007/s12975-021-00925-1. Epub 2021 Jun 25.

SDF-1α/CXCR4 Pathway Mediates Hemodynamics-Induced Formation of Intracranial Aneurysm by Modulating the Phenotypic Transformation of Vascular Smooth Muscle Cells

Yazhou Yan #  1   2 , Jiachao Xiong #  3 , Fengfeng Xu #  4 , Chuanchuan Wang  1 , Zhangwei Zeng  1 , Haishuang Tang  4 , Zhiwen Lu  1 , Qinghai Huang  5
Affiliations

SDF-1α/CXCR4 Pathway Mediates Hemodynamics-Induced Formation of Intracranial Aneurysm by Modulating the Phenotypic Transformation of Vascular Smooth Muscle Cells

Yazhou Yan et al. Transl Stroke Res. 2022 Apr.

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.

Keywords: Intracranial aneurysms; Phenotypic transformation; SDF-1α/CXCR4 signaling pathway; Vascular remodeling; Vascular smooth muscle cells.

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