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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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and Methods<\/jats:title><jats:p>NO\u2010Tie 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\u2010Tie mice. Given the previously documented beneficial effect of VEGF signaling, we tested whether NO\u2010Tie\u2010VEGF 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\u2010Tie\u2010VEGF compared with NO\u2010Tie mice. Using soluble Dll4 (sDll4), we stimulated Notch signaling in the ischemic muscles of mice. NO\u2010Tie\u2010sDll4 mice had significantly increased capillary and arteriole densities, but impaired blood flow recovery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/micc.12549","type":"journal-article","created":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T06:39:24Z","timestamp":1555051164000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide\u2010angiopoietin signaling in a mouse model of peripheral ischemia"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-4809","authenticated-orcid":false,"given":"Maria J. C.","family":"Machado","sequence":"first","affiliation":[{"name":"Division of Cancer and Stem Cells Tumour and Vascular Biology Laboratories, Cancer Biology School of Medicine Queen's Medical Centre University of Nottingham Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Boardman","sequence":"additional","affiliation":[{"name":"Division of Cancer and Stem Cells Tumour and Vascular Biology Laboratories, Cancer Biology School of Medicine Queen's Medical Centre University of Nottingham Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Riu","sequence":"additional","affiliation":[{"name":"Division of Cancer and Stem Cells Tumour and Vascular Biology Laboratories, Cancer Biology School of Medicine Queen's Medical Centre University of Nottingham Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Costanza","family":"Emanueli","sequence":"additional","affiliation":[{"name":"National Heart &amp; Lung Institute Imperial College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew V.","family":"Benest","sequence":"additional","affiliation":[{"name":"Division of Cancer and Stem Cells Tumour and Vascular Biology Laboratories, Cancer Biology School of Medicine Queen's Medical Centre University of Nottingham Nottingham UK"},{"name":"COMPARE University of Birmingham and University of Nottingham Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David O.","family":"Bates","sequence":"additional","affiliation":[{"name":"Division of Cancer and Stem Cells Tumour and Vascular Biology Laboratories, Cancer Biology School of Medicine Queen's Medical Centre University of Nottingham Nottingham UK"},{"name":"COMPARE University of Birmingham and University of Nottingham Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,6,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61249-0"},{"key":"e_1_2_8_3_1","first-page":"5233","article-title":"Long\u2010term survival of patients with critical limb ischemia treated with iloprost: response rate and predictive criteria. 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