Regulation of the endothelial translatome by arterial stiffening in atherosclerosis
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abstract
Arterial stiffening precedes the development of increased blood pressure and atherosclerotic lesions. Increased endothelial permeability and adhesiveness in response to vascular wall stiffening, particularly in lesion-prone areas of the arterial tree, constitute the earliest detectable changes in atherosclerosis. However, how the interplay between altered arterial wall biomechanics and atheroprone hemodynamics regulates molecular pathways underlying endothelial dysfunction remains unknown. The objective in this application is to determine regionally unique, stiffening-dependent changes in the endothelial translatome, i.e. the entire set of mRNAs recruited to ribosomes for protein synthesis, during early, pre-lesion stages of atherosclerosis. The hypothesis is that comparative analysis of the endothelial translatome associated with lesion-prone vs. lesion-resistant aortic regions will identify new modules of coregulated genes and signaling pathways underlying endothelial dysfunction. To test this hypothesis, arterial stiffness will be experimentally manipulated in a new atheroprone mouse model that allows inducible, endothelial-specific expression of an epitope-tagged ribosomal protein. Affinity purification of translating ribosomes will be coupled with RNA-Seq and bioinformatics to identify region-specific changes in the endothelial translatome of soft vs. stiff aortas obtained before or after atherosclerotic lesion development. By identifying modules of coregulated genes underlying endothelial dysfunction during early, pre-lesion stages of atherosclerosis, this research is expected to have a positive impact on the discovery of novel targets for effective interventions to confer atheroprotection
