SLC44A2, also known as CTL2 (choline transporter–like protein 2), is a gene located on chromosome 19p13.2 with 24 exons. SLC44A2 plays a crucial role in choline and ethanolamine transport and uptake (10, 11). SLC44A2 is expressed in variety of human tissues, including the inner ear, lung, kidney, and blood cells (10), and is located in the mitochondrion membrane and cell membrane. Genome-wide association studies (GWAS) have identified SLC44A2 as a critical factor closely linked with several human phenotypes, such as hearing loss, lung jury, Ménière disease, and venous thrombosis (12, 13). However, its role in cardiovascular disease remains unknown.

Song and colleagues (7) provide compelling evidence that SLC44A2-mediated VSMC phenotypic switching plays an essential role in the pathogenesis of AA (Figure 1). The authors initially observed changes in SLC44A2 expression between primary mouse aortic smooth muscle cells (MASMCs) from saline-infused mice and those from angiotensin II–infused (Ang II–infused) mice. Analysis of single-cell RNA sequencing (scRNA-seq) data demonstrated predominant SLC44A2 expression in VSMCs. Notably, both Ang II–infused mice and human aortic smooth muscle cells (HASMCs) displayed increased SLC44A2 expression. Furthermore, SLC44A2 levels were upregulated in human patients with abdominal AA (AAA), indicating a crucial role for SLC44A2 in AA development. The authors further investigated the regulatory role of SLC44A2 in the VSMC phenotypic switch by silencing or overexpressing SLC44A2 in HASMCs or MASMCs. Knockdown of SLC44A2 suppressed HASMC or MASMC contractility, whereas overexpression of SLC44A2 enhanced VSMC contractile markers (ACTA2 and TAGLN) and repressed synthetic markers (OPN and KLF4), along with reduced MMP activity. Importantly, reintroduction of SLC44A2 into SLC44A2-deficient HASMCs or MASMCs inhibited the phenotypic switch of VSMCs from a contractile to synthetic state. These data indicate that SLC44A2 is of vital importance in preserving VSMCs’ contractile phenotype.

SLC44A2 mediates the VSMC phenotypic switch in aortic aneurysm. (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.

Song and authors further examined the role of SLC44A2 in AA progression using Apoe–/– TaglnCre/+ mice. Overexpression of SLC44A2 by injecting lentivirus carrying an Slc44a2 overexpression plasmid (Lenti-Slc44a2) ameliorated Ang II–induced elastin damage, medial degeneration, and arterial dilatation, suggesting a protective role of SLC44A2 in AA. Conversely, SLC44A2 deficiency in mice (Slc44a2SMKO mice) aggregated the VSMC phenotypic switch to the synthetic state and exacerbated AA progression. Collectively, these data demonstrated that SLC44A2-mediated regulation of the VSMC phenotype is critical in AA progression, highlighting its potential as a therapeutic target in managing AAs (7).