Slc44a2, encoding the choline transporter-like protein CTL2, is involved in multiple biological functions. It plays a role in platelet aggregation, neutrophil activation, and is associated with pathways like TGF-β/SMAD signaling [1,2,3]. It also has implications in maintaining cerebrovascular homeostasis and is related to blood phenotypes due to genetic polymorphisms [3,5]. Genetic models, such as knockout mice, have been crucial for studying its functions.

In aortic aneurysm, VSMC-specific Slc44a2-knockout mice are more susceptible to aortic aneurysm under Ang II infusion. Slc44a2 silencing promotes VSMCs toward a synthetic phenotype, while overexpression attenuates VSMC phenotypic switching. Mechanistically, it interacts with NRP1 and ITGB3 to activate TGF-β/SMAD signaling, promoting contractile gene expression [1,2]. In venous thrombosis, Slc44a2-deficient mice have a reduced response in the stenosis-driven venous thrombosis model but not in the hypercoagulability-driven one. This indicates its role in the initiation of venous thrombosis, potentially related to platelet-neutrophil interaction [4]. In mesenchymal lung cells, Slc44a2 deletion leads to altered adhesion protein expression, reduced adhesion, and enhanced proliferation [6]. Also, Slc44a2 null mice have increased bleeding times and delayed thrombosis, as it mediates choline transport into mitochondria for platelet activation [7].

In conclusion, Slc44a2 is essential for various biological processes, including cell adhesion, proliferation, platelet activation, and VSMC phenotypic regulation. Gene-knockout mouse models have been instrumental in revealing its role in diseases such as aortic aneurysm and venous thrombosis, providing insights into potential therapeutic strategies for these conditions.

References:

1. Song, Tianyu, Zhao, Shuang, Luo, Shanshan, Xie, Liping, Ji, Yong. 2024. SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm. In The Journal of clinical investigation, 134, . doi:10.1172/JCI173690. https://pubmed.ncbi.nlm.nih.gov/38916960/

2. Xing, Mengen, Chen, Wanqi, Ji, Yachen, Song, Weihong. 2024. SLC44A2-mediated phenotypic switch of vascular smooth muscle cells contributes to aortic aneurysm. In The Journal of clinical investigation, 134, . doi:10.1172/JCI183527. https://pubmed.ncbi.nlm.nih.gov/39145443/

3. Koehl, Bérengère, Vrignaud, Cédric, Mikdar, Mahmoud, Azouzi, Slim, Peyrard, Thierry. 2023. Lack of the human choline transporter-like protein SLC44A2 causes hearing impairment and a rare red blood phenotype. In EMBO molecular medicine, 15, e16320. doi:10.15252/emmm.202216320. https://pubmed.ncbi.nlm.nih.gov/36695047/

4. Tilburg, Julia, Coenen, Daniëlle M, Zirka, Gaia, Maracle, Chrissta X, Thomas, Grace M. 2020. SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis. In Journal of thrombosis and haemostasis : JTH, 18, 1714-1727. doi:10.1111/jth.14835. https://pubmed.ncbi.nlm.nih.gov/32297475/

5. Wang, Yufeng, Chen, Xihui, Chen, Qi, Wu, Yuanming, Wang, Li. 2022. SLC44A2 Frequency, a New TaqMan Real-Time Polymerase Chain Reaction Method for HNA-3A/3B Genotyping, and a New Application of Droplet Digital PCR. In Frontiers in genetics, 13, 794285. doi:10.3389/fgene.2022.794285. https://pubmed.ncbi.nlm.nih.gov/35646052/

6. Nair, Thankam S, Kakaraparthi, Bala Naveen, Yang, Lucy, Kanicki, Ariane, Carey, Thomas E. 2021. Slc44a2 deletion alters tetraspanin and N-cadherin expression: Reduced adhesion and enhanced proliferation in cultured mesenchymal lung cells. In Tissue & cell, 73, 101599. doi:10.1016/j.tice.2021.101599. https://pubmed.ncbi.nlm.nih.gov/34371293/

7. Bennett, J Allen, Mastrangelo, Michael A, Ture, Sara K, Morrell, Craig N, Lowenstein, Charles J. 2020. The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function. In Nature communications, 11, 3479. doi:10.1038/s41467-020-17254-w. https://pubmed.ncbi.nlm.nih.gov/32661250/