LATS1/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis

Area of Science:

• Cardiovascular Biology
• Endothelial Cell Biology
• Molecular Mechanisms of Atherosclerosis

Background:

• Atherothrombosis, a key driver of acute coronary syndromes, arises from intraplaque thrombosis, often in disturbed blood flow (d-flow) regions.
• Endothelial cells (ECs) sense blood flow via mechanotransduction, with LATS1/2 (large tumor suppressor kinases 1 and 2) being known regulators.
• The precise mechanisms linking d-flow, EC senescence, proliferation, and intraplaque thrombosis remain incompletely understood.

Purpose of the Study:

• To elucidate the EC-specific roles of LATS1/2 in the development of atherothrombosis.
• To investigate the molecular and metabolic changes in ECs under conditions of disturbed blood flow.
• To identify potential therapeutic targets for preventing intraplaque thrombosis.

Main Methods:

• Generation of inducible EC-specific LATS1/2 knockout mice using a partial carotid ligation model.
• Spatial multiomics analysis of human and mouse atherosclerotic plaques via imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics.
• Pharmacological inhibition of key identified molecular targets.

Main Results:

• EC-specific homozygous deletion of LATS1/2 led to severe edema and vascular permeability, while heterozygous/homozygous deletion allowed survival and spontaneous atherothrombotic plaque formation with neovascularization.
• LATS1/2 loss induced a senescence-associated stemness phenotype in ECs, characterized by CD38 upregulation and altered mitochondrial metabolism, including sulfite/taurine accumulation and SUOX deficiency.
• This metabolic reprogramming sustained EC proliferation under energetic stress, promoting fragile neovessels and intraplaque thrombosis; CD38 inhibition partially rescued these phenotypes.
• Similar EC states were observed in human atherosclerotic plaques.

Conclusions:

• Loss of LATS1/2 in ECs triggers a CD38-driven senescence-associated stemness phenotype, promoting intraplaque thrombosis via mitochondrial metabolic reprogramming.
• This study defines a mechanistic link between disturbed blood flow, EC metabolic reprogramming, and the pathogenesis of atherothrombosis and hemorrhage.
• Targeting CD38 may offer a therapeutic strategy to mitigate LATS1/2-dependent atherothrombotic processes.