Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and
Stefano Tarantini1, Zsuzsanna Tucsek1, M Noa Valcarcel-Ares1
1Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Insights
Insulin-like Growth Factor 1 (IGF-1) deficiency worsens hypertension-induced damage to brain blood vessels, impacting memory and cognitive function. This study highlights IGF-1
Area of Science:
- Neuroscience
- Endocrinology
- Cardiovascular Science
Background:
- Age and hypertension impair cerebral microcirculation, contributing to vascular cognitive impairment (VCI) and Alzheimer's disease.
- Microvascular rarefaction in the hippocampus is linked to cognitive decline.
- Age-related decline in Insulin-like Growth Factor 1 (IGF-1) affects cerebral microvessels, but its role in hippocampal microvascularization is unclear.
Purpose of the Study:
- To investigate the combined effects of IGF-1 deficiency and hypertension on hippocampal microvascular density.
- To analyze gene expression related to angiogenesis and microvascular regression in the hippocampus under these conditions.
Main Methods:
- Hypertension was induced in mice using angiotensin II infusion.
- Mice included controls and those with IGF-1 deficiency (Igf1f/f + TBG-Cre-AAV8).
- Microvascular density and gene expression in the hippocampus and neocortex were assessed.
Main Results:
- IGF-1 deficiency reduced microvascular density.
- IGF-1 deficiency exacerbated hypertension-induced microvascular rarefaction in the hippocampus and neocortex.
- Hypertensive IGF-1 deficient mice showed an anti-angiogenic gene expression profile in the hippocampus.
Conclusions:
- Adult-onset IGF-1 deficiency negatively impacts cerebral microcirculation, reducing capillarity and worsening hypertension-induced rarefaction.
- These microvascular impairments, alongside other factors, likely contribute to VCI pathogenesis in elderly hypertensive individuals.
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 regression in the hippocampus. To achieve that goal, we induced hypertension in control and IGF-1 deficient mice (Igf1 f/f + TBG-Cre-AAV8) 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 both in the hippocampus and the neocortex. The anti-angiogenic hippocampal gene expression signature observed in hypertensive IGF-1 deficient mice in the present study provides important clues for subsequent studies to elucidate mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of VCI. In conclusion, adult-onset, isolated endocrine IGF-1 deficiency exerts deleterious effects on the cerebral microcirculation, leading to a significant decline in cortical and hippocampal capillarity and exacerbating hypertension-induced cerebromicrovascular rarefaction. The morphological impairment of the cerebral microvasculature induced by IGF-1 deficiency and hypertension reported here, in combination with neurovascular uncoupling, increased blood-brain barrier disruption and neuroinflammation reported in previous studies likely contribute to the pathogenesis of vascular cognitive impairment in elderly hypertensive humans.
