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IGF‐1 deficiency exacerbates hypertension‐induced cerebromicrovascular rarefaction in mice: implications for cognitive decline
Author(s) -
Tarantini Stefano,
Giles Cory,
Toth Peter,
Ashpole Nicole M,
Tucsek Zsuzsanna,
ValcarcelAres Marta Noa,
Gautam Tripti,
Sonntag William E,
Wren Jonathan D,
Csiszar Anna,
Ungvari Zoltan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.728.3
Subject(s) - endocrinology , microcirculation , medicine , cognitive decline , angiogenesis , hippocampus , hippocampal formation , pdgfrb , biology , gene , biochemistry , disease , dementia
Aging is associated with marked deficiency in circulating insulin‐like growth factor (IGF‐1), which has been shown to contribute to age‐related cognitive decline. The mechanisms by which IGF‐1 deficiency impairs brain function are multifaceted and likely involve impairment of cerebral microcirculation. Accordingly, previously we have shown that IGF‐1 deficiency impairs cerebromicrovascular endothelial function, neurovascular coupling and adaptation of myogenic autoregulatory mechanisms to hypertension, contributing to blood‐brain barrier disruption and neuroinflammation. The present study was designed to characterize the effects of IGF‐1 deficiency on microvascular density in the brain and its pathogenic role in hypertension‐induced microvascular injury. Circulating IGF‐1 deficiency was induced in mice by AAV‐mediated knockdown of IGF‐1 in the liver ( Igf1 f/f +TBG‐Cre‐AAV8). Hypertension was induced by chronic infusion of angiotensin‐II. We found that circulating IGF‐1 deficiency is associated with decreased microvascular density and exacerbates hypertension‐induced microvascular rarefaction in the cortex and the hippocampus. Hippocampal microvascular rarefaction positively correlated with impairment of hippocampal‐dependent cognitive function. To elucidate the mechanisms underlying the synergistic effects of hypertension and IGF‐1 deficiency on microvascular density hippocampal mRNA expression of genes involved in regulation of angiogenesis and microvascular regression was assessed using a targeted qPCR array. Both hypertension and IGF‐1 deficiency appear to decrease the expression of a number of genes involved in the maintenance of the structural integrity of the cerebral microcirculation (e.g. Vegfb, Pdgfrb ), while increasing the expression of genes promoting endothelial apoptosis and/or microvascular regression (e.g. Tnfa , Angpt2 ). Gene set enrichment analysis scores calculated for positive and negative regulators of angiogenesis suggest that interaction of hypertension in IGF‐1 deficiency results in an exacerbated negative angiogenesis signature. Collectively, IGF‐1 deficiency promotes cerebromicrovascular rarefaction and exacerbates hypertension‐induced structural damage to the cerebral microcirculation, which likely contribute to the deleterious effects of age‐related IGF‐1 deficiency on higher brain function in the elderly. Support or Funding Information This work was supported by grants from the American Heart Association and the National Institute on Aging