Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2.
OBJECTIVE
Comprehensive understanding of the mechanisms regulating angiogenesis might provide new strategies for angiogenic therapies for treating diverse physiological and pathological ischemic conditions. The E-twenty six (ETS) factor Ets variant 2 (ETV2; aka Ets-related protein 71) is essential for the formation of hematopoietic and vascular systems. Despite its indispensable function in vessel development, ETV2 role in adult angiogenesis has not yet been addressed. We have therefore investigated the role of ETV2 in vascular regeneration.


APPROACH AND RESULTS
We used endothelial Etv2 conditional knockout mice and ischemic injury models to assess the role of ETV2 in vascular regeneration. Although Etv2 expression was not detectable under steady-state conditions, its expression was readily observed in endothelial cells after injury. Mice lacking endothelial Etv2 displayed impaired neovascularization in response to eye injury, wounding, or hindlimb ischemic injury. Lentiviral Etv2 expression in ischemic hindlimbs led to improved recovery of blood perfusion with enhanced vessel formation. After injury, fetal liver kinase 1 (Flk1), aka VEGFR2, expression and neovascularization were significantly upregulated by Etv2, whereas Flk1 expression and vascular endothelial growth factor response were significantly blunted in Etv2-deficient endothelial cells. Conversely, enforced Etv2 expression enhanced vascular endothelial growth factor-mediated endothelial sprouting from embryoid bodies. Lentiviral Flk1 expression rescued angiogenesis defects in endothelial Etv2 conditional knockout mice after hindlimb ischemic injury. Furthermore, Etv2(+/-); Flk1(+/-) double heterozygous mice displayed a more severe hindlimb ischemic injury response compared with Etv2(+/-) or Flk1(+/-) heterozygous mice, revealing an epistatic interaction between ETV2 and FLK1 in vascular regeneration.


CONCLUSIONS
Our study demonstrates a novel obligatory role for the ETV2 in postnatal vascular repair and regeneration.
['Park|Changwon|C|', 'Lee|Tae-Jin|TJ|', 'Bhang|Suk Ho|SH|', 'Liu|Fang|F|', 'Nakamura|Rei|R|', 'Oladipupo|Sunday S|SS|', 'Pitha-Rowe|Ian|I|', 'Capoccia|Benjamin|B|', 'Choi|Hong Seo|HS|', 'Kim|Tae Min|TM|', 'Urao|Norifumi|N|', 'Ushio-Fukai|Masuko|M|', 'Lee|Dong Jun|DJ|', 'Miyoshi|Hiroyuki|H|', 'Kim|Byung-Soo|BS|', 'Lim|Dae-Sik|DS|', 'Apte|Rajendra S|RS|', 'Ornitz|David M|DM|', 'Choi|Kyunghee|K|']
D042501:Angiogenic Proteins D000818:Animals D002478:Cells, Cultured D020256:Choroidal Neovascularization D004195:Disease Models, Animal D042783:Endothelial Cells D005786:Gene Expression Regulation D018014:Gene Transfer Techniques D005822:Genetic Vectors D006579:Heterozygote D006614:Hindlimb D007511:Ischemia D016086:Lentivirus D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D018482:Muscle, Skeletal D018919:Neovascularization, Physiologic D010641:Phenotype D020127:Recovery of Function D012038:Regeneration D015398:Signal Transduction D012867:Skin D013997:Time Factors D014157:Transcription Factors D042461:Vascular Endothelial Growth Factor A D040301:Vascular Endothelial Growth Factor Receptor-2 D014945:Wound Healing
regeneration endothelial cells hematopoietic systems hindlimb ischemia