Abstract
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. To study aging-related sFlt1 change and its impact on ischemia-induced neovascularization, a hindlimb ischemia model was applied to young and aged mice. 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. Immnunofluorescence showed that Flt-1 was co-localized with CD11b+ macrophages of aged ischemic muscles. Hypoxia stimulated sFlt1 expression in CD11b+ cells of aged bone-marrow (BM), and this effect was diminished by siWnt5a. The cultured medium of aged mice BM-derived CD11b+ cells suppressed human endothelial cell (EC) and endothelial progenitor cell (EPC) angiogenic actions induced by VEGF, and these decreases were improved by treatment with siWnt5a-conditioned medium. Thus, aging appears to decline neovascularization in response to ischemic stress via the VEGFR2/Akt signaling inactivation in ECs and ECPs that is mediated by Wnt5a/SC35 axis activated macrophages-derived sFlt1 production in advanced age.
Highlights
The mechanism by which angiogenesis declines with aging is not fully understood
On postoperative day 14, quantitative immunostaining revealed that the aged mice had lower capillary density in non-ischemic and ischemic muscles compared to the young mice (Fig. 1C, D), suggesting that aging impairs vascular regenerative capacity
As a first step to investigate whether aging affects on plasma sFlt1 level, we monitored the changes in the levels of plasma sFlt1 in young and aged mice (Fig. 2A)
Summary
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. Aging appears to decline neovascularization in response to ischemic stress via the VEGFR2/Akt signaling inactivation in ECs and ECPs that is mediated by Wnt5a/SC35 axis activated macrophages-derived sFlt production in advanced age. SFlt and Angiogenesis in Aged Mice dysfunction and decreases in the numbers and intrinsic function of bone-marrow (BM)-derived endothelial progenitor cells (EPCs), a shift in the balance between vascular cell apoptosis and proliferation, and changes in the extracellular microenvironment (e.g., alterations in growth factors, inflammatory cytokines, and oxidative stress) [2,3,4,5]. We used the in vitro experimental strategies that to investigate the molecular mechanisms of the aging-related decline in the vascular regeneration capacity in aged mice with a special focus on macrophage Wnt/SC35-sFlt axis activation and endothelial cell (EC) VEGFR2/Akt signaling inactivation
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