Enhanced Notch signaling modulates unproductive revascularization in response to Nitric Oxide-Angiopoietin signaling in a mouse model of peripheral ischemia.

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Summary of "Enhanced Notch signaling modulates unproductive revascularization in response to Nitric Oxide-Angiopoietin signaling in a mouse model of peripheral ischemia."

Arteriolargenesis can be induced by concomitant stimulation of Nitric Oxide (NO)-Angiopoietin receptor (Tie)-Vascular Endothelial Growth Factor (VEGF) signaling in the rat mesentery angiogenesis assay. We hypothesized that the same combination of exogenously added growth factors would have a positive impact on the recovery of blood flow in a model of unilateral hindlimb ischemia. NO-Tie mice had faster blood flow recovery compared to control mice, as assessed by laser speckle imaging. There was no change in capillary density within the ischemic muscles, but arteriole density was higher in NO-Tie mice. Surprisingly, NO-Tie-VEGF mice recovered no differently than control, arteriole density was similar and capillary density was lower. Dll4 is a driver of arterial specification, so we hypothesized that Notch1 expression would be involved in arteriolargenesis. There was a significant upregulation of Notch1 transcripts in NO-Tie-VEGF compared with NO-Tie mice. Using soluble Dll4 (sDll4), we stimulated Notch signaling in the ischemic muscles. NO-Tie-sDll4 mice had significantly increased capillary and arteriole densities, but impaired blood flow recovery. These results suggest that early Dll4 activation can lead to unproductive angiogenesis and arteriolargenesis, despite increased vascular densities. These results suggest spatial and temporal balance of growth factors needs to be perfected for functional revascularisation. This article is protected by copyright. All rights reserved.


Journal Details

This article was published in the following journal.

Name: Microcirculation (New York, N.Y. : 1994)
ISSN: 1549-8719
Pages: e12549


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