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

Geroscience. 2024 Jun;46(3):3481-3501. doi: 10.1007/s11357-024-01090-7. Epub 2024 Feb 23.

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-CreERT2 Igf1rf/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.

Keywords: Aging brain; Cerebral microhemorrhage; Cerebrovascular aging; Insulin-like growth factor 1; Vascular cognitive impairment; Vascular smooth muscle cells.

MeSH terms

  • Aged
  • Animals
  • Gait
  • Humans
  • Hypertension* / complications
  • Hypertension* / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Mice
  • Muscle, Smooth, Vascular
  • Quality of Life
  • Receptor, IGF Type 1* / genetics

Substances

  • Receptor, IGF Type 1
  • Insulin-Like Growth Factor I