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

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.