Increased propensity for cerebral microhemorrhages in a IGF‐1 deficient mouse model of accelerated vascular aging

Abstract

Clinical and experimental studies show that aging exacerbates hypertension‐induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes IGF‐1 deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF‐1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver‐specific knockdown of IGF‐1 (Igf1f/f + TBG‐Cre‐AAV8) and control mice by angiotensin‐II plus L‐NAME treatment. In IGF‐1 deficient mice the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging increased oxidative stress‐mediated MMP activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension‐induced cerebrovascular oxidative stress and MMP activation were increased in IGF‐1 deficient mice. We found that IGF‐1 deficiency, by impairing hypertension‐induced adaptive media hypertrophy and extracellular matrix remodeling, also perturbs arteriolar remodeling processes, which act to restore circumferential stress, preventing mechanical damage to the vascular wall. Collectively, IGF‐1 deficiency promotes the pathogenesis CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that up‐regulate IGF‐1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress and MMP activation may be useful for the prevention of CMHs, protecting neurocognitive function in high‐risk elderly patients.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on Aging