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

Abstract

Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimer’s disease. Recent advances in geroscience, including results from studies on heterochronic parabiosis models, reinforce the hypothesis that cell non-autonomous mechanisms play a key role in regulating cerebrovascular aging processes. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert multifaceted vasoprotective effects and production of both hormones is significantly reduced in aging. This brief overview focuses on the role of age-related GH/IGF-1 deficiency in the development of cerebrovascular pathologies and VCID. It explores the mechanistic links among alterations in the somatotropic axis, specific macrovascular and microvascular pathologies (including capillary rarefaction, microhemorrhages, impaired endothelial regulation of cerebral blood flow, disruption of the blood brain barrier, decreased neurovascular coupling, and atherogenesis) and cognitive impairment. Improved understanding of cell non-autonomous mechanisms of vascular aging is crucial to identify targets for intervention to promote cerebrovascular and brain health in older adults.

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

“…There is growing evidence that age-related impairments in the structure and function of the cerebral microcirculation are causally linked to cognitive decline. 8,15,48,[55][56][57][58][59][60][61][62][63] Our findings highlight the critical impact of anti-geronic IGF-1 signaling on cerebromicrovascular endothelial cells and underline its significance in maintaining the functional and structural integrity of the cerebral microcirculatory system.…”

“…IGF1R deletion in these cells could have some level of indirect outcomes on brain vascular endothelial cells. Based on our recently published results, circulating factors have striking effect on the vasculature, especially on endothelial cells; thus, it is very difficult to completely dissect these mechanisms in a living organism; therefore, we were focusing on the brain endothelium‐related consequences 55,100 . It is also important to mention that it is still unclear which brain vascular region is the most effected by endothelial senescence in this accelerated aging model.…”

“…Based on our recently published results, circulating factors have striking effect on the vasculature, especially on endothelial cells; thus, it is very difficult to completely dissect these mechanisms in a living organism; therefore, we were focusing on the brain endothelium-related consequences. 55,100 It is also important to mention that it is still unclear which brain vascular region is the most effected by endothelial senescence in this accelerated aging model. We assume based on our presented BBB permeability results and our previous studies, that the capillary endothelial cells are mostly affected by increased senescence.…”

IGF1R deficiency in vascular smooth muscle cells impairs myogenic autoregulation and cognition in mice

“…These factors contribute to cognitive impairment, balance and mobility defects, and other adverse consequences. Extensive evidence has demonstrated the role of the somatotropic axis in cerebrovascular aging, in particular, a role for insulin-like growth factor 1 (IGF-1) ( Bickel et al, 2023a ). IGF-1 is mainly produced by the liver, but also within the brain, and levels decrease with age.…”

“…VSMC phenotypic changes are also a part of the vascular response in cerebrovascular diseases such as ischemic and hemorrhagic stroke ( Chen et al, 2013 ; Poittevin et al, 2014 ; Wu et al, 2016 ). Growth factors, including IGF-1, are key regulators of VSMC phenotypic switching, for example IGF-1 plays a protective role in atherosclerotic plaque stability through its actions on VSMCs, and we recently demonstrated that IGF-1 induces cellular hypertrophy and altered expression of ECM genes and ECM remodeling genes in cultured primary rat VSMCs ( Risinger et al, 2006 ; von der Thusen et al, 2011 ; Fulop et al, 2019b ; Bickel et al, 2023a , b ). A potential role for IGF-1 on brain VSMCs is highlighted by our previous studies showing that mice with circulating IGF-1 deficiency exhibit pathological cerebrovascular arterial wall ECM remodeling in response to hypertension and impaired cerebrovascular autoregulation ( Fulop et al, 2019b ).…”