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Angiogenesis

, Volume 21, Issue 3, pp 557–569 | Cite as

Peripheral post-ischemic vascular repair is impaired in a murine model of Alzheimer’s disease

  • Tatyana Merkulova-Rainon
  • Chris S. Mantsounga
  • Dong Broquères-You
  • Cristina Pinto
  • José Vilar
  • Diana Cifuentes
  • Philippe Bonnin
  • Nathalie Kubis
  • Daniel Henrion
  • Jean-Sébastien Silvestre
  • Bernard I. Lévy
Original Paper
  • 159 Downloads

Abstract

The pathophysiology of sporadic Alzheimer’s disease (AD) remains uncertain. Along with brain amyloid-β (Aβ) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (− 29%, P < 0.001), collateral recruitment (− 24%, P < 0.001), capillary density (− 22%; P < 0.01) and arteriole density (− 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Aβ in the hind limb; thus, circulating Aβ is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-β1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD.

Keywords

Alzheimer’s disease Vascular dysfunction Hind limb ischemia Vascular repair Angiogenesis 

Abbreviations

Amyloid beta

AD

Alzheimer’s disease

ANOVA

Analysis of variance

APP

Amyloid precursor protein

CLI

Critical limb ischemia

ECE

Endothelin-converting enzyme

ET-1

Endothelin-1

FAL

Femoral artery ligation

HIF-1α

Hypoxia-inducible factor-1α

FGF-2

Fibroblast growth factor-2

NO

Nitric oxide

PDGF-BB

Platelet-derived growth factor-BB

PLGF-2

Placental growth factor-2

SDF-1

Stromal cell-derived factor-1

TGF-β1

Transforming growth factor- 1

VEGF

Vascular endothelial growth factor

VEGFR2

Vascular endothelial growth factor receptor-2

WT

Wild-type control littermates

Notes

Acknowledgements

This work was partly supported by the French National Research Agency Grant ANR-12-MALZ-0006, the Fondation de France and the France Alzheimer Association. C.M. received a Grant from the Fondation pour la Recherche Médicale (FDT20140930795) and JSS, a Grant from the French National Research Agency (ANR-13-BSV1-0015-01).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10456_2018_9608_MOESM1_ESM.docx (48 kb)
Supplementary material 1 (DOCX 48 kb)

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Authors and Affiliations

  1. 1.Institut des Vaisseaux et du SangParis Cedex 10France
  2. 2.INSERM U965ParisFrance
  3. 3.INSERM U970ParisFrance
  4. 4.Université Paris Diderot, Sorbonne Paris CitéParisFrance
  5. 5.AP-HP, Hôpital LariboisièreParisFrance
  6. 6.UMR CNRS 6015 - INSERM U1083AngersFrance

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