Igf-1 Deficiency Exacerbates Hypertension-Induced Cerebral Microhemorrhages In Mice, Mimicking The Aging Phenotype

Recent studies demonstrate that age-related IGF-1 deficiency exacerbates hypertension-induced cognitive decline, but the underlying mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to impair neuronal function. To determine whether IGF-1 deficiency exacerbates hypertension-induced CMHs, mice with liver-specific knockdown of IGF-1 (Igf1f/f + TBG-iCre-AAV8) and control mice were treated with angiotensin-II plus L-NAME. We found that the same level of hypertension lead to significantly earlier onset and increased incidence of CMHs in IGF-1 deficient mice than in control mice, as shown by neurological examination, gait analysis and histological assessment of CMHs in serial brain sections. Previous studies showed that oxidative stress-mediated MMP activation importantly contribute to the pathogenesis of CMHs. Thus, it is significant that high pressure-induced oxidative stress (DHE fluorescence; control: 1±0.2 vs. IGF-1 deficient: 2.4±0.2, p<0.01) and redox-sensitive activation of MMPs (IGF-1 deficient: 5±1.9 fold increase vs. control, p<0.01) are increased in cerebral arteries isolated from IGF-1 deficient mice. Collectively, IGF-1 deficiency promotes CMHs in mice, 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.