Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia

Machado, Maria J.C.; Boardman, Rachel; Riu, Federica; Emanueli, Costanza; Benest, Andrew V.; Bates, David O

Abstract

Introduction
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 also have a positive impact on arteriolargenesis and, consequently, the recovery of blood flow in a model of unilateral hindlimb ischemia.

Results and Methods
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. Given the previously documented beneficial effect of VEGF signaling, we tested whether NO?Tie?VEGF mice would show further improvement. Surprisingly, these mice recovered no differently from 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 of mice. NO?Tie?sDll4 mice had significantly increased capillary and arteriole densities, but impaired blood flow recovery.

Conclusion
These results suggest that Dll4 activation early on in revascularization 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 ideal functional and anatomical revascularisation.

Citation

Machado, M. J., Boardman, R., Riu, F., Emanueli, C., Benest, A. V., & Bates, D. O. (2019). Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia. Microcirculation, 26(6), https://doi.org/10.1111/micc.12549

• Journal Article Type: Article
• Acceptance Date: Apr 3, 2019
• Online Publication Date: Apr 11, 2019
• Publication Date: 2019-08
• Deposit Date: May 20, 2019
• Publicly Available Date: Jul 31, 2019
• Journal: Microcirculation
• Print ISSN: 1073-9688
• Electronic ISSN: 1549-8719
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: 6
• Article Number: e12549
• DOI: https://doi.org/10.1111/micc.12549
• Keywords: Physiology (medical); Physiology; Molecular Biology; Cardiology and Cardiovascular Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/1775360
• Publisher URL: https://onlinelibrary.wiley.com/doi/full/10.1111/micc.12549
• Additional Information: This is the peer reviewed version of the following article: Machado, MJC, Boardman, R, Riu, F, Emanueli, C, Benest, AV, Bates, DO. Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide?angiopoietin signaling in a mouse model of peripheral ischemia. Microcirculation. 2019; 00:e12549, which has been published in final form at https://doi.org/10.1111/micc.12549.; This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.