SLC44A2-mediated phenotypic switch of vascular smooth muscle cells contributes to aortic aneurysm
Mengen Xing, … , Yachen Ji, Weihong Song
Mengen Xing, … , Yachen Ji, Weihong Song
Published August 15, 2024
Citation Information: J Clin Invest. 2024;134(16):e183527. https://doi.org/10.1172/JCI183527.
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Commentary Vascular biology

SLC44A2-mediated phenotypic switch of vascular smooth muscle cells contributes to aortic aneurysm

Abstract

The phenotypic switch of vascular smooth cells (VSMCs) from a contractile to a synthetic state is associated with the development and progression of aortic aneurysm (AA). However, the mechanism underlying this process remains unclear. In this issue of the JCI, Song et al. identified SLC44A2 as a regulator of the phenotypic switch in VSMCs. Inhibition of SLC44A2 facilitated the switch to the synthetic state, contributing to the development of AA. Mechanistically, SLC44A2 interacted with NRP1 and ITGB3 to activate the TGF-β/SMAD signaling pathway, resulting in VSMCs with a contractile phenotype. Furthermore, VSMC-specific SLC44A2 overexpression by genetic or pharmacological manipulation reduced AA in mouse models. These findings suggest the potential of targeting the SLC44A2 signaling pathway for AA prevention and treatment.

Authors

Mengen Xing, Wanqi Chen, Yachen Ji, Weihong Song

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Figure 1

SLC44A2 mediates the VSMC phenotypic switch in aortic aneurysm.

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SLC44A2 mediates the VSMC phenotypic switch in aortic aneurysm. (A) The ...
(A) The switch from a contractile to a synthetic state is crucial for the development and progression of aortic aneurysm. SLC44A2 functions as a scaffolding protein that regulates the TGF-β/SMAD signaling pathway by forming a complex with NRP1 and ITGB3. This complex facilitates the release of activated TGF-β from latent TGF-β (latency-associated peptide [LAP]), which then binds to TGF-β receptors (TGFBRs) on the cell membrane, initiating the downstream phosphorylation of SMAD2/3. p-SMAD2/3 then translocates into the nucleus, where it regulates the expression of contractile markers ACTA2 and TAGLN, or synthetic markers KLF4 and OPN, associated with the VSMC phenotypic switch. SLC44A2 deficiency induced by siSLC44A2 disrupts the association between NRP1 and ITGB3, reduces the levels of TGF-β and p-SMAD2, and promotes the expression of synthetic VSMC markers KLF4 and OPN, while suppressing contractile VSMC markers ACTA2 and TAGLN, further contributing to the pathogenesis of aortic aneurysm. (B) RUNX1 acts as a key regulator of SLC44A2 by binding to the SLC44A2 promoter region and transcriptionally activating SLC44A2 gene expression. Lenalidomide (LEN), an activator of RUNX1, enhances SLC44A2 expression, boosting the SLC44A2/NRP1/ITGB3/TGF-β/SMAD signaling pathway. This promotes the expression of VSMC contractile markers ACTA2 and TAGLN, and represses synthetic VSMC markers KLF4 and OPN, inhibiting the phenotypic switching of VSMCs from a contractile to a synthetic state, ultimately suppressing the development of aortic aneurysm.