2. Academic Validation
  3. CAD drives Angiotensin II-induced vascular smooth muscle cell activation via upregulation of pyrimidine biosynthesis and rRNA synthesis

CAD drives Angiotensin II-induced vascular smooth muscle cell activation via upregulation of pyrimidine biosynthesis and rRNA synthesis

  • Life Sci. 2026 Sep 15:401:124530. doi: 10.1016/j.lfs.2026.124530.
Mun-Ju Park 1,  Daehoon Kim 1,  Keun-Gyu Park 2,  Gui-Hwa Jeong 3,  Jun-Kyu Byun 4,  Yeon-Kyung Choi 5
Affiliations

Affiliations

  • 1 Department of Biomedical Science, Kyungpook National University, Daegu, 41566, South Korea.
  • 2 Department of Biomedical Science, Kyungpook National University, Daegu, 41566, South Korea; Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, South Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, South Korea.
  • 3 Departmentof Internal Medicine, CHA Gumi Medical Center, CHA University, Gumi, 39295, South Korea. Electronic address: [email protected].
  • 4 Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, 41566, South Korea. Electronic address: [email protected].
  • 5 Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, South Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, 41404, South Korea. Electronic address: [email protected].
PMID: 42264140 DOI: 10.1016/j.lfs.2026.124530
Abstract

Aims: Vascular smooth muscle cell (VSMC) phenotypic switching is a hallmark of vascular remodeling in diseases such as restenosis and atherosclerosis. Although Angiotensin II (Ang II) promotes VSMC proliferation and migration through various signaling pathways, the role of nucleotide metabolism remains poorly understood. This study investigates the functional significance of CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase), a rate-limiting enzyme in de novo pyrimidine biosynthesis, in Ang II-induced VSMC activation and pathological vascular remodeling.

Materials and methods: Primary VSMCs were stimulated with Ang II to induce phenotypic switching. A mouse carotid artery ligation model was used to study neointimal hyperplasia in vivo. VSMC proliferation and migration were assessed via EdU incorporation and Transwell assays, respectively. The functional role of CAD expression was interrogated through pharmacological inhibition and gene silencing. Molecular mechanisms, including ribosomal RNA (rRNA) synthesis and protein translation, were analyzed using Western blotting and qPCR.

Key findings: Ang II stimulation and vascular injury significantly increased CAD expression and phosphorylation. This activation enhanced rRNA synthesis and translation of remodeling-associated proteins, including intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9). Uridine supplementation rescued phenotypic defects caused by CAD silencing, confirming that pyrimidine biosynthesis sustains the pathological VSMC phenotype. Furthermore, CAD inhibition attenuated Ang II-induced VSMC proliferation and migration in vitro and reduced neointimal hyperplasia in vivo.

Significance: Our findings identify nucleotide metabolism as a central determinant of VSMC pathology. By linking biosynthetic signaling to translational control, CAD represents a promising therapeutic target for proliferative vascular diseases.

Keywords

CAD; Pyrimidine biosynthesis; Ribosome biogenesis; Vascular disease; Vascular smooth muscle cells.

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