Changes in Mirna Expression Patterns and Vascular Aging Phenotypes in Mice with Developmental Liver-Specific Knockdown of Igf-1

The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in the anabolic hormone IGF‐1 during adolescence. There is increasing experimental and clinical evidence that alterations in IGF‐1 levels during development regulate multiple aspects of the aging process and affect the incidence of multiple age‐related diseases, including cardiovascular and cerebrovascular diseases. The present study was designed to characterize the effect of developmental IGF‐1 deficiency on the vascular aging phenotype. To achieve that goal early‐onset, isolated endocrine IGF‐1 deficiency was induced mice by developmental knockdown of IGF‐1 specifically in the liver using Cre‐lox technology ( Igf1 f/f mice crossed with mice expressing albumin‐driven Cre recombinase). The animals were studied at an age representing ~75% of maximal lifespan potential, which corresponds to the biological age of a ~67 year old human. To assess vascular health endothelium‐dependent vasorelaxation and vascular ROS production were tested. Due to the emergence of miRNAs as important regulators of vascular aging phenotype, miRNA expression profile in the aorta of mice with developmental IGF‐1 deficiency was also tested. We found that aging was associated with endothelial dysfunction, which was unaffected by developmental IGF‐1 deficiency. We identified 19 miRNAs that were differentially expressed in the aortas of aged mice and 11 miRNAs that were differentially expressed miRNAs in aortas of mice with developmental IGF‐1 deficiency. GO terms enriched among predicted targets for miRNAs differentially expressed with age in the aorta include cytokine production, chromatin silencing, intracellular protein transport and regulation of apoptotic cell death. GO terms enriched among predicted targets for miRNAs differentially expressed with developmental IGF‐1 deficiency in the aorta include regulation of apoptotic cell death, blood vessel remodeling and intracellular protein transport. Collectively, developmental IGF‐1 deficiency is associated with a vascular miRNA expression profile later in life that likely plays a role in development of age‐related vascular pathologies. Support or Funding Information This work was supported by grants from the American Heart Association and the National Institute on Aging