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

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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.

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Abbreviations

Aβ:

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

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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).

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  1. Tatyana Merkulova-Rainon and Chris S. Mantsounga have contributed equally to this work.

Authors and Affiliations

  1. Institut des Vaisseaux et du Sang, 8 rue Guy Patin, 75475, Paris Cedex 10, France

    Tatyana Merkulova-Rainon, Chris S. Mantsounga, Dong Broquères-You, Cristina Pinto, Diana Cifuentes & Bernard I. Lévy

  2. INSERM U965, 41 boulevard de la Chapelle, 75475, Paris, France

    Tatyana Merkulova-Rainon, Dong Broquères-You, Diana Cifuentes, Philippe Bonnin & Nathalie Kubis

  3. INSERM U970, 56 rue Leblanc, 75908, Paris, France

    Chris S. Mantsounga, Cristina Pinto, José Vilar, Jean-Sébastien Silvestre & Bernard I. Lévy

  4. Université Paris Diderot, Sorbonne Paris Cité, 75205, Paris, France

    Philippe Bonnin, Nathalie Kubis & Bernard I. Lévy

  5. AP-HP, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475, Paris, France

    Philippe Bonnin & Nathalie Kubis

  6. UMR CNRS 6015 - INSERM U1083, 3 rue Roger Amsler, 49100, Angers, France

    Daniel Henrion

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Merkulova-Rainon, T., Mantsounga, C.S., Broquères-You, D. et al. Peripheral post-ischemic vascular repair is impaired in a murine model of Alzheimer’s disease. Angiogenesis 21, 557–569 (2018). https://doi.org/10.1007/s10456-018-9608-7

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