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

• Published in: GeroScience Vol. 46; no. 3; pp. 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: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-06-2024; Springer Nature B.V
• 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; Aging brain; Vascular cognitive impairment; Insulin-like growth factor 1; Vascular smooth muscle cells; Cerebrovascular aging; Cerebral microhemorrhage
• ISSN: 2509-2723; 2509-2715; 2509-2723
• DOI: 10.1007/s11357-024-01090-7

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.