The process of vascular remodeling is a complex phenomenon in which the equilibrium between vascular cells and the internal environment is disrupted, particularly in the context of cardiovascular diseases. Angiotensin II (Ang II) has been demonstrated to induce vascular remodeling and contribute to the development of vascular diseases by regulating functions of vascular smooth muscle cells (SMCs). The objective of this study is to elucidate the pathophysiological mechanisms underlying vascular remodeling in greater detail.

We obtained vascular specimens from clinical coronary artery bypass grafting (CABG) surgeries and successfully established a human primary aortic SMC model. By using varying concentrations of Ang II, we observed that Ang II promotes the proliferation of SMCs and slightly affects their migration ability. We further employed a multi-omics approach—including untargeted proteomics, metabolomics, and lipidomics—utilizing mass spectrometry (MS) to analyze the alterations induced by different dosage of Ang II in human primary SMCs. Multi-omics analysis identified a total of 8,382 proteins, 239 metabolites, and 797 lipids. Among the 528 differentially expressed proteins (DEPs), we observed abnormal deposition of extracellular matrix (ECM) proteins, along with perturbations of RhoA and Rac1 proteins, revealing alterations in the cytoskeleton and cell motility of SMCs.

The multi-omics data obtained from Ang II-treated and control SMCs were integrated to identify significantly altered molecules. Subsequent analyses, including pathway enrichment and interaction network assessments, were conducted to pinpoint critical pathways underlying Ang II-induced vascular remodeling. Notably, the upregulation of numerous pro-inflammatory cytokines, including IL6 and TGFB1, indicated a heightened inflammatory response. This inflammatory response was further confirmed through lysophosphatidylcholine (LPC) accumulation in the lipidomic dataset. By combining the lipidomic and proteomic datasets, we observed an upregulation of the DNA replication pathway and a downregulation of the phosphatidylserine (PS), suggesting increased cell proliferation and inhibition of apoptosis. Furthermore, the integration of proteomic and metabolomic data collectively revealed significant alterations in energy metabolism, specifically in the pentose phosphate pathway (PPP), indicating an altered energy pattern during cell proliferation process.

These findings revealed phenotypic changes and energetic remodeling in VSMCs under Ang II treatment, highlighting a regulatory role for VSMCs in the vascular remodeling process.