The Role of Endothelial Cells in Atherosclerosis: Insights from Genetic Association Studies

This expert review synthesized findings from genome-wide association studies (GWAS), functional genomics, and high-throughput CRISPR screens to characterize the role of endothelial cells (ECs) in coronary artery disease — arguing that endothelial biology is a causal, not merely consequential, contributor to atherosclerosis.

Over 350 CAD loci have been identified by GWAS, the majority involving non-lipid mechanisms. Among these, EC gene expression shows the strongest enrichment for CAD genetic risk of any cell type — stronger than smooth muscle cells, macrophages, or hepatocytes. Rare loss-of-function variants in NOS3 (encoding endothelial nitric oxide synthase) causally increase CAD risk, confirming the NO signaling pathway as a direct causal mechanism beyond the LDL-cholesterol axis. High-throughput CRISPR screens are now accelerating the identification of EC-specific regulators of atherosclerosis, with the CCM (cerebral cavernous malformation)/shear stress pathway emerging as a common regulator of multiple CAD-relevant EC programs.

The clinical implication is that the future of cardiovascular pharmacology extends beyond lipid lowering. Endothelial-targeted therapies — addressing NO bioavailability, flow-sensitive EC programs, and EC-specific gene variants — could complement statins and PCSK9 inhibitors in reducing residual risk. This review frames the biological rationale for such strategies.

We rate the evidence strong for a review article. A rigorous synthesis of genetics and EC biology establishing endothelial dysfunction as a causally relevant and potentially targetable pathway in atherosclerosis.