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 3

VSMC overexpression of SLC44A2 moderates aortic aneurysm in Ang II–infused Apoe–/– mice.

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VSMC overexpression of SLC44A2 moderates aortic aneurysm in Ang II–infus...
(A) Eight-week-old male Apoe–/– TaglnCre/+ mice were intravenously injected with lentivirus containing control vector or the reverse Slc44a2 sequence with 2 loxP sites. After 2 weeks, osmotic pumps were implanted subcutaneously to infuse saline or Ang II (1,000 ng/kg/min) for 28 days. (B) The systolic blood pressure at 0, 7, 14, 21, and 28 days after osmotic pump implantation. n = 8–11. NS, no significance. (C) The incidence of aortic aneurysm in Ang II–infused mice. n = 11. (D) Representative morphology of aortas from saline- or Ang II–infused mice. Scale bars: 5 mm. n = 11. (E) Ultrasound images and inner diameter quantification of the suprarenal abdominal aorta. n = 8–11. (F) Electron microscopic images of the suprarenal abdominal aorta. Red arrowheads indicate elastin breaks. El, elastin; Nu, nucleus. Scale bars: 5 μm. n = 3. (G) Hematoxylin and eosin (H&E) and elastic Verhoeff–Van Gieson (EVG) staining of the suprarenal abdominal aorta. Red arrowheads indicate elastin breaks. n = 6. (H) Immunofluorescence images of in situ zymography (DQ gelatin, green) in the suprarenal abdominal aorta. Scale bars: 200 μm. n = 6. (I) Immunofluorescent staining for OPN (red), ACTA2 (green), and staining with DAPI (blue) in the suprarenal abdominal aorta. Scale bars: 200 μm. n = 6. Differences were analyzed by 2-way ANOVA with mixed effects followed by Tukey’s multiple-comparison test (B), Fisher’s exact test (C), Welch’s ANOVA followed by Tamhane’s T2 multiple-comparison test (E and H), or 1-way ANOVA followed by Tukey’s multiple-comparison test or Welch’s ANOVA followed by Tamhane’s T2 multiple-comparison test (I).