How Senescent Plaque Cells Trigger Thrombosis via a Hidden Metabolic Switch

Atherothrombosis—the formation of blood clots triggered by atherosclerotic plaque rupture or erosion—is responsible for most heart attacks and strokes. Disturbed blood flow at arterial branch points is a known driver of plaque instability, but the molecular mechanisms linking mechanical force sensing in endothelial cells (ECs) to intraplaque thrombosis have remained poorly understood. This study addresses that gap by focusing on LATS1 and LATS2, the core kinases of the Hippo pathway that mediate endothelial mechanotransduction.

Using tamoxifen-inducible, EC-specific knockout (EKO) mice, the team showed that complete loss of both LATS1 and LATS2 was lethal due to fatal vascular edema and barrier failure. However, a partial deletion model—heterozygous LATS1 loss combined with homozygous LATS2 deletion—produced viable mice that spontaneously developed atherothrombotic plaques with neovascularization, closely mimicking advanced human disease. These mice were also studied in a partial carotid ligation model that induces disturbed flow.

Spatial multi-omics approaches, including imaging mass cytometry, COMET™ sequential immunofluorescence, and spatial metabolomics, revealed a striking endothelial phenotype within plaques: a 'senescence-associated stemness' (SAS) state in which cells simultaneously expressed senescence markers and retained proliferative capacity. This SAS state was driven by upregulation of CD38, a NAD+-consuming enzyme. CD38 suppressed sulfite oxidase (SUOX), causing accumulation of sulfite and taurine—metabolic signatures of mitochondrial dysfunction. Mechanistically, CD38 activity switched mitochondrial complex V from its ATP-synthesizing role into reverse (ATP-consuming) mode, dramatically depleting cellular energy. Cells compensated by upregulating glutamate catabolism and TCA cycle flux, sustaining proliferation despite energetic stress. The resulting neovessels were structurally fragile, leaky, and prone to hemorrhage, creating a prothrombotic microenvironment inside plaques.

Pharmacological inhibition of CD38 attenuated the SAS phenotype, restored more normal metabolic function, and reduced intraplaque thrombosis in the mouse model. Critically, the same CD38-associated SAS EC state was identified in advanced human atherosclerotic plaques using spatial proteomics, validating translational relevance. The authors note that conventional murine atherosclerosis models do not fully recapitulate this human phenotype, underscoring the importance of their partial EKO model.

This work establishes the LATS1/2–CD38 axis as a mechanistic bridge connecting disturbed hemodynamic forces to endothelial metabolic reprogramming and plaque thrombogenicity. It opens new avenues for stage-specific interventions targeting endothelial metabolism in atherothrombotic disease, with CD38 inhibition emerging as a pharmacologically tractable strategy.