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

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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.

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Acknowledgments

This work was supported by grants from the American Heart Association (to ST, MNVA, PT, AC, ZT, and ZU), the National Center for Complementary and Alternative Medicine (R01-AT006526 to ZU), the National Institute on Aging R01-AG047879 to AC; R01-AG038747 to WES, R01-NS056218 to AC and WES; 5U54GM104938 to JYW, the Arkansas Claude Pepper Older Americans Independence Center at University of Arkansas Medical Center (to JYW and ZU; P30 AG028718), the Oklahoma Center for the Advancement of Science and Technology (to AC, ZU, WES), the Oklahoma IDeA Network for Biomedical Research Excellence (to AC), the Oklahoma Nathan Shock Center of Excellence in the Biology of Aging (P30 AG050911 to JDW and WES), and the Reynolds Foundation (to WES, ZU and AC).

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Authors and Affiliations

  1. Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Stefano Tarantini, Zsuzsanna Tucsek, M. Noa Valcarcel-Ares, Peter Toth, Tripti Gautam, Cory B. Giles, Jonathan D. Wren, Nicole M. Ashpole, William E. Sonntag, Zoltan Ungvari & Anna Csiszar

  2. Department of Physiology, University of Pecs, Pecs, Hungary

    Peter Toth, Zoltan Ungvari & Anna Csiszar

  3. Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program, Oklahoma City, OK, USA

    Cory B. Giles & Jonathan D. Wren

  4. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA

    Cory B. Giles & Jonathan D. Wren

  5. Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA

    Praveen Ballabh

  6. Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children’s Hospital at Westchester Medical Center- New York Medical College, Valhalla, NY, USA

    Praveen Ballabh

  7. Reynolds Institute on Aging and Department of Geriatrics, University of Arkansas for Medical Science, 4301 West Markham Street, No. 748, Little Rock, AR, 72205, USA

    Jeanne Y. Wei

  8. Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, 72205, USA

    Jeanne Y. Wei

  9. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    William E. Sonntag, Zoltan Ungvari & Anna Csiszar

Authors
  1. Stefano Tarantini
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  2. Zsuzsanna Tucsek
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  3. M. Noa Valcarcel-Ares
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  4. Peter Toth
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  5. Tripti Gautam
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  6. Cory B. Giles
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  7. Praveen Ballabh
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  8. Jeanne Y. Wei
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  9. Jonathan D. Wren
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  10. Nicole M. Ashpole
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  11. William E. Sonntag
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  12. Zoltan Ungvari
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  13. Anna Csiszar
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Corresponding author

Correspondence to Anna Csiszar.

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The authors declare that they have no competing interests.

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Stefano Tarantini, Zsuzsanna Tucsek, and M. Noa Valcarcel-Ares contributed equally to this manuscript.

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Tarantini, S., Tucsek, Z., Valcarcel-Ares, M.N. et al. Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging. AGE 38, 273–289 (2016). https://doi.org/10.1007/s11357-016-9931-0

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