Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

Abstract

Strong epidemiological and experimental evidence indicate that both age and hypertension lead to significant functional and structural impairment of the cerebral microcirculation, predisposing to the development of vascular cognitive impairment (VCI) and Alzheimer's disease. Preclinical studies establish a causal link between cognitive decline and microvascular rarefaction in the hippocampus, an area of brain important for learning and memory. Age-related decline in circulating IGF-1 levels results in functional impairment of the cerebral microvessels; however, the mechanistic role of IGF-1 deficiency in impaired hippocampal microvascularization remains elusive. The present study was designed to characterize the additive/synergistic effects of IGF-1 deficiency and hypertension on microvascular density and expression of genes involved in angiogenesis and microvascular AGE (2016) 38:273-289

Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype

“…qPCR data were normalized using quantile normalization, and then, for each sample, the binary fragility vector was compared to negative normalized Ct values using Spearman's rank correlation coefficient (Spearman's ρ) as reported (Tarantini et al ., 2016b). This ‘vascular fragility signature’, therefore, measures the combined expression levels of positive and negative regulators of vascular fragility: a higher value indicates higher expression of profragility genes and lower expression of antifragility genes.…”

“…Expression of genes related to the pathogenesis of CMHs was determined by qPCR; 67 genes analyzed (Table S1) were manually annotated as being provascular fragility and antifragility, and this data were converted into a binary vector (1 for profragility genes and À1 for antifragility genes). qPCR data were normalized using quantile normalization, and then, for each sample, the binary fragility vector was compared to negative normalized Ct values using Spearman's rank correlation coefficient (Spearman's q) as reported (Tarantini et al, 2016b). This 'vascular fragility signature', therefore, measures the combined expression levels of positive and negative regulators of vascular fragility: a higher value indicates higher expression of profragility genes and lower expression of antifragility genes.…”

“…Epidemiological evidence suggests that low IGF‐1 levels increase the risk for cerebromicrovascular diseases (Sonntag et al ., 2013). Previous research demonstrated that rodent models with decreases of circulating IGF‐1 levels also exhibit aging‐like vascular phenotypes including cerebromicrovascular autoregulatory dysfunction, manifestation of intracerebral hemorrhages, neurovascular uncoupling, increased vascular oxidative stress, dysregulation of genes encoding the ECM, and impaired functional adaptation of cerebral arteries to hypertension (Bailey‐Downs et al ., 2012; Sonntag et al ., 2013; Toth et al ., 2014, 2015a; Tarantini et al ., 2016a,b). Despite these advances, the pathophysiological link between age‐related circulating IGF‐1 deficiency and the development of CMHs has never been studied.…”

“…To test our hypothesis, we used a novel mouse model of isolated endocrine IGF‐1 deficiency induced by adeno‐associated viral knockdown of IGF‐1 specifically in the mouse liver using Cre‐lox technology ( Igf1 f/f  + TBG‐Cre‐AAV8; Toth et al ., 2014, 2015a; Tarantini et al ., 2016a,b). We induced hypertension in IGF‐1‐deficient mice and respective controls (by treatment with angiotensin II [Ang II] and the NO synthesis inhibitor l ‐NAME) and compared the incidence, size, and localization of CMHs.…”

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

“…The highly conserved insulin/IGF pathway has been extensively studied [14,[66][67][68][69][70][71][72] in the context of aging and neurodegeneration [11,73]. While early evidence suggested that lower levels of IGF-1 were beneficial for lifespan, recent extensive studies indicate that these findings were limited to C. elegans and drosophila that exhibit common insulin/IGF-1 receptor pathways [15].…”