Abstract 17654: The Soluble VEGF Receptor sFlt-1 Contributes to Impaired Neovascularization in Aged Mice

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Introduction: The mechanism by which angiogenesis declines with aging is not fully understood. Soluble vascular endothelial growth factor receptor 1 (VEGFR1) form (sFlt1) contributes to endothelial dysfunction in pathological conditions. However, the roles of sFlt1 in ischemia-induced neovascularizationof aged animals have not been investigated.

Objectives: Here, we investigated aging-related sFlt1 change and its impact on ischemia-induced neovascularization

Methods: aAhindlimb ischemia model was applied to young (2-month-old) and aged (>18-month-old) mice (n=15 for young mice; n=16 for aged mice).

Results: A serial laser Doppler blood flow imaging assay revealed that the blood flow recovery remained impaired throughout the follow-up period. At day 14, immunostaining showed lesser capillary formation in the aged mice. An ELISA showed that the aged mice had increased plasma sFlt-1 levels at indicated time points after surgery. On operative day 4, the aged ischemic muscles had decreased levels of p-VEGFR2 and p-Akt and increased levels of sFlt-1, Wnt5a, and SC35 genes or/and protein as well as increased numbers of inflammatory cells (macrophages and leucocytes) and matrix metalloproteinase-9 activity. Double immnunofluorescence showed that Flt-1 was co-localized with CD11b+ macrophages of aged ischemic muscles. Hypoxia stimulated sFlt1 expression in cultured CD11b+ cells of aged bone-marrow (BM), and this effect was diminished by siWnt5a treatment. The cultured medium of aged mice BM-derived CD11b+ cells under hypoxia suppressed human umbilical vein endothelial cell and endothelial progenitor cell angiogenic actions induced by VEGF, and these decreases were improved by treatment with siWnt5a-conditioned medium.

Conclusions: Thus, aging appears to decline vascular regeneration in ischemic states through its ability to activate Wnt5a/SC35-sFlt1-mediated VEGFR2/Akt signaling pathway in advanced age.

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