Increased Susceptibility to Cerebral Microhemorrhages Is Associated With Imaging Signs of Microvascular Degeneration in the Retina in an Insulin-Like Growth Factor 1 Deficient Mouse Model of Accelerated Aging

Abstract

Age-related cerebrovascular defects contribute to vascular cognitive impairment and dementia (VCID) as well as other forms of dementia. There has been great interest in developing biomarkers and other tools for studying cerebrovascular disease using more easily accessible tissues outside the brain such as the retina. Decreased circulating insulin-like growth factor 1 (IGF-1) levels in aging are thought to contribute to the development of cerebrovascular impairment, a hypothesis that has been supported by the use of IGF-1 deficient animal models. Here we evaluate vascular and other retinal phenotypes in animals with circulating IGF-1 deficiency and ask whether the retina mimics common age-related vascular changes in the brain such as the development of microhemorrhages. Using a hypertension-induced model, we confirm that IGF-1 deficient mice exhibited worsened microhemorrhages than controls. The retinas of IGF-1 deficient animals do not exhibit microhemorrhages but do exhibit signs of vascular damage and retinal stress such as patterns of vascular constriction and Müller cell activation. These signs of retinal stress are not accompanied by retinal degeneration or impaired neuronal function. These data suggest that the role of IGF-1 in the retina is complex, and while IGF-1 deficiency leads to vascular defects in both the brain and the retina, not all brain pathologies are evident in the retina.

Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis

“…CBF is measured in the somatosensory cortex before and after whisker stimulation, and the increased CBF following stimulation is reflective of NVC response. Stimulation-induced increases in CBF were much lower in circulating IGF-1 deficient mice compared to controls ( 113 , 116 ). This impairment of NVC in IGF-1 deficiency supports a protective role for IGF-1 in vascular function.…”

“…Older adults with low circulating IGF-1 levels have 39% higher risk of cardiovascular mortality ( 112 ). Animal models of circulating IGF-1 deficiency serve as models of accelerated aging ( 18 , 21 , 93 , 113 – 120 ), mimicking many age-related cerebrovascular pathologies.…”

“…CMHs are thought to arise due to a combination of age-associated factors that lead to increased microvascular fragility including: 1) structural defects such as impaired hypertension-induced adaptive changes in the ECM and impaired protective hypertrophy in the medial layer, 2) functional defects such as impaired myogenic autoregulation, and 3) age-related cellular and molecular changes such as increased oxidative stress and MMP activation ( 93 , 114 , 115 ). These age-associated factors are significantly affected by IGF-1 deficiency, and IGF-1 deficiency in mouse models of accelerated aging significantly exacerbates the development of CMHs ( 93 , 113 ).…”

Endothelial deficiency of insulin‐like growth factor‐1 receptor leads to blood–brain barrier disruption and accelerated endothelial senescence in mice, mimicking aspects of the brain aging phenotype

“…Increased oxidative stress and consequential increases in cellular DNA damage are important mechanisms of endothelial senescence. Considering the previously documented protective effects of IGF‐1 against oxidative stress and other cellular stressors, 13,14,16–18,47,73–81 we hypothesize that endothelial‐specific knockdown of IGF1R would impede these protective effects. Our results accord with emerging evidence that IGF‐1 may play a critical role in modulating cellular senescence in various age‐related diseases, such as atherosclerosis 70–72 .…”

Associations of Circulating Insulin-Growth Factor-1 With Cognitive Functions and Quality of Life Domains in Ambulatory Young Adults With Cerebral Palsy: A Pilot Study

“…Supporting our accelerated aging phenomenon hypothesis ( 2 ). Another study showed that IGF-1 deficient mice exhibited worsened microhemorrhages, suggesting that the pro-vascular and protective effects of circulating IGF-1 in the preservation of brain health and maintenance of cognitive function ( 47 ).…”