Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging.
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 (Igf1f/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.
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Stefano
S
Tarantini
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Zsuzsanna
Z
Tucsek
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
M Noa
MN
Valcarcel-Ares
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Physiology, University of Pecs, Pecs, Hungary.
Peter
P
Toth
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Tripti
T
Gautam
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program, Oklahoma City, OK, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA.
Cory B
CB
Giles
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA.|Department of Pediatrics, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center- New York Medical College, Valhalla, NY, USA.
Praveen
P
Ballabh
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.|Geriatric Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, 72205, USA.
Jeanne Y
JY
Wei
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program, Oklahoma City, OK, USA.|Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA.
Jonathan D
JD
Wren
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Nicole M
NM
Ashpole
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
William E
WE
Sonntag
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.|Department of Physiology, University of Pecs, Pecs, Hungary.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
Zoltan
http://orcid.org/0000-0002-6035-6039
Z
Ungvari
Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. anna-csiszar@ouhsc.edu.|Department of Physiology, University of Pecs, Pecs, Hungary. anna-csiszar@ouhsc.edu.|The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. anna-csiszar@ouhsc.edu.
Anna
A
Csiszar
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000804:Angiotensin II / Q000009:adverse effects / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001812:Blood-Brain Barrier / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000503:physiopathology; D015870:Gene Expression; D006624:Hippocampus / Q000098:blood supply*; D006801:Humans; D006973:Hypertension / Q000150:complications*; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000073436:Microvascular Rarefaction / Q000209:etiology / Q000473:pathology*; D019579:Neocortex / Q000098:blood supply*; D012333:RNA, Messenger / Q000378:metabolism
D015415:Biomarkers; D012333:RNA, Messenger; C519530:insulin-like growth factor-1, mouse; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I
Alzheimer’s disease; Brain aging; Cerebral blood flow; Dementia; Ischemia; Mild cognitive impairment; Vascular aging