SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm
Tianyu Song, … , Liping Xie, Yong Ji
Tianyu Song, … , Liping Xie, Yong Ji
Published June 25, 2024
Citation Information: J Clin Invest. 2024;134(16):e173690. https://doi.org/10.1172/JCI173690.
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SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm

Abstract

Aortic aneurysm is a life-threatening disease with limited interventions that is closely related to vascular smooth muscle cell (VSMC) phenotypic switching. SLC44A2, a member of the solute carrier series 44 (SLC44) family, remains undercharacterized in the context of cardiovascular diseases. Venn diagram analysis based on microarray and single-cell RNA sequencing identified SLC44A2 as a major regulator of VSMC phenotypic switching in aortic aneurysm. Screening for Slc44a2 among aortic cell lineages demonstrated its predominant location in VSMCs. Elevated levels of SLC44A2 were evident in the aorta of both patients with abdominal aortic aneurysm and angiotensin II–infused (Ang II–infused) Apoe–/– mice. In vitro, SLC44A2 silencing promoted VSMCs toward a synthetic phenotype, while SLC44A2 overexpression attenuated VSMC phenotypic switching. VSMC-specific SLC44A2-knockout mice were more susceptible to aortic aneurysm under Ang II infusion, while SLC44A2 overexpression showed protective effects. Mechanistically, SLC44A2’s interaction with NRP1 and ITGB3 activates TGF-β/SMAD signaling, thereby promoting contractile gene expression. Elevated SLC44A2 in aortic aneurysm is associated with upregulated runt-related transcription factor 1 (RUNX1). Furthermore, low-dose lenalidomide (LEN; 20 mg/kg/day) suppressed aortic aneurysm progression by enhancing SLC44A2 expression. These findings reveal that the SLC44A2-NRP1-ITGB3 complex is a major regulator of VSMC phenotypic switching and provide a potential therapeutic approach (LEN) for aortic aneurysm treatment.

Authors

Tianyu Song, Shuang Zhao, Shanshan Luo, Chuansheng Chen, Xingeng Liu, Xiaoqi Wu, Zhongxu Sun, Jiawei Cao, Ziyu Wang, Yineng Wang, Bo Yu, Zhiren Zhang, Xiaolong Du, Xiaoqiang Li, Zhijian Han, Hongshan Chen, Feng Chen, Liansheng Wang, Hong Wang, Kangyun Sun, Yi Han, Liping Xie, Yong Ji

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Figure 1

Aortic SLC44A2 expression is elevated in aortic aneurysm.

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Aortic SLC44A2 expression is elevated in aortic aneurysm. (A) Venn diagr...
(A) Venn diagram showing the overlap between VSMC phenotype–related genes, differentially expressed markers for VSMCs, DEGs in human aortic aneurysm (GSE47472), and DEGs in VSMCs niched in mouse aortic aneurysm (GSE186865). (B) MASMCs were isolated from the whole abdominal aortas of saline- or Ang II–infused mice. The mRNA levels of Slc44a2, Uchl1, Dkk3, Anxa3, and Cryab were detected by qRT-PCR. n = 5. (C) Uniform manifold approximation and projection (UMAP) visualization of single cells from abdominal aortic tissue of mice (GSE152583). Cells were partitioned into 8 major lineages: vascular smooth muscle cells (VSMCs), fibroblasts (Fibro), endothelial cells (EC), macrophages (MΦ), T cells (T), B cells (B), erythrocytes (Eryth), and dendritic cells (DC). (D) Slc44a2 expression among distinct cellular populations. (E and F) Apoe–/– mice were infused with saline or Ang II for 28 days. (E) Immunofluorescent staining for SLC44A2 (red), ACTA2 (white), and staining with DAPI (blue) in the suprarenal abdominal aorta. Elastic fibers are green (autofluorescence). Arrowheads indicate elastin breaks. IgG was used as the isotype control. Scale bars: 200 μm. n = 5. (F) Slc44a2 mRNA level in aorta. n = 5. (G) Western blot analysis of SLC44A2 expression in the aorta from non-AAA groups and AAA patients. n = 6. (H) SLC44A2 mRNA level in the aorta from non-AAA groups and AAA patients. n = 6. (I) Immunofluorescent staining for SLC44A2 (red), ACTA2 (green), and staining with DAPI (blue) in the aortic media of non-AAA groups and AAA patients. IgG was used as the isotype control. L, lumen. Scale bars: 40 μm. n = 6. Differences were analyzed by unpaired, 2-tailed Student’s t test (B, F, and H), Welch’s ANOVA followed by Tamhane’s T2 multiple-comparison test or 1-way ANOVA followed by Tukey’s multiple-comparison test (E), Welch’s t test (G), or Welch’s ANOVA followed by Tamhane’s T2 multiple-comparison test (I).