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

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.
Source :
GeroScience; Jun2024, Vol. 46 Issue 3, p3481-3501, 21p
Publication Year :
2024

Abstract

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<superscript>ERT2</superscript> Igf1r<superscript>f/f</superscript>) 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
25092715
Volume :
46
Issue :
3
Database :
Complementary Index
Journal :
GeroScience
Publication Type :
Academic Journal
Accession number :
178047170
Full Text :
https://doi.org/10.1007/s11357-024-01090-7