Context-specific effects of CCM2 on atherosclerosis

Ccm2+/- mice show reduced atherosclerosis after 12 weeks on a high-fat, high-cholesterol diet, but increased inflammatory signaling and atherosclerotic burden after 20 weeks.

• Why it matters: CCM2 variants are linked to coronary artery disease, yet how CCM2 shapes atherosclerosis across disease stages is unclear.
• What they did: The study combined human genetics, Perturb-seq–guided transcriptional profiling in human aortic endothelial cells, and single-cell profiling in mouse atherosclerosis models, testing reduced CCM2 signaling across timepoints.
• The result: Baseline endothelial and human EC phenotypes were more anti-inflammatory (including increased KLF2 and reduced monocyte adhesion and procoagulant activity), but protection was not sustained: after 12 weeks Ccm2+/- had higher circulating TNF and more inflammatory programs, and after 20 weeks had greater atherosclerotic burden; rs2107732 showed lower CAD risk in the general population but higher risk in cardiometabolic-enriched trial cohorts.

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