Vascular smooth muscle cell-specific Igf1r deficiency exacerbates the development of hypertension-induced cerebral microhemorrhages and gait defects

Cerebrovascular fragility and cerebral microhemorrhages (CMH) contribute to age-related cognitive impairment, mobility defects, and vascular cognitive impairment and dementia, impairing healthspan and reducing quality of life in the elderly. Insulin-like growth factor 1 (IGF-1) is a key vasoprotecti...

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Bibliographic Details
Published in:GeroScience 2024-06, Vol.46 (3), p.3481-3501
Main Authors: Miller, Lauren R., Bickel, Marisa A., Vance, Michaela L., Vaden, Hannah, Nagykaldi, Domonkos, Nyul-Toth, Adam, Bullen, Elizabeth C., Gautam, Tripti, Tarantini, Stefano, Yabluchanskiy, Andriy, Kiss, Tamas, Ungvari, Zoltan, Conley, Shannon M.
Format: Article
Language:English
Subjects:
Aged
Aging
Angiotensin
Angiotensin II
Animals
Biomedical and Life Sciences
Cell Biology
Cognitive ability
Dementia disorders
Gait
Gait Disorders, Neurologic - genetics
Geriatrics
Geriatrics/Gerontology
Humans
Hypertension
Hypertension - complications
Hypertension - genetics
Inflammation
Insulin-like growth factor I
Insulin-Like Growth Factor I - metabolism
Insulin-like growth factors
Life Sciences
Mice
Molecular Medicine
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
NG-Nitroarginine methyl ester
Original Article
Phenotypes
Quality of life
Receptor, IGF Type 1 - genetics
Smooth muscle
Vascular dementia
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Summary:Cerebrovascular fragility and cerebral microhemorrhages (CMH) contribute to age-related cognitive impairment, mobility defects, and vascular cognitive impairment and dementia, impairing healthspan and reducing quality of life in the elderly. Insulin-like growth factor 1 (IGF-1) is a key vasoprotective growth factor that is reduced during aging. Circulating IGF-1 deficiency leads to the development of CMH and other signs of cerebrovascular dysfunction. Here our goal was to understand the contribution of IGF-1 signaling on vascular smooth muscle cells (VSMCs) to the development of CMH and associated gait defects. We used an inducible VSMC-specific promoter and an IGF-1 receptor (Igf1r) floxed mouse line ( Myh11-Cre ERT2 Igf1r f/f ) to knockdown Igf1r. Angiotensin II in combination with L-NAME-induced hypertension was used to elicit CMH. We observed that VSMC-specific Igf1r knockdown mice had accelerated development of CMH, and subsequent associated gait irregularities. These phenotypes were accompanied by upregulation of a cluster of pro-inflammatory genes associated with VSMC maladaptation. Collectively our findings support an essential role for VSMCs as a target for the vasoprotective effects of IGF-1, and suggest that VSMC dysfunction in aging may contribute to the development of CMH.
ISSN:2509-2723
2509-2715
2509-2723
DOI:10.1007/s11357-024-01090-7