TY - JOUR
T1 - Perivascular cell-specific knockout of the stem cell pluripotency gene Oct4 inhibits angiogenesis
AU - Hess, Daniel L.
AU - Kelly-Goss, Molly R.
AU - Cherepanova, Olga A.
AU - Nguyen, Anh T.
AU - Baylis, Richard A.
AU - Tkachenko, Svyatoslav
AU - Annex, Brian H.
AU - Peirce, Shayn M.
AU - Owens, Gary K.
N1 - Funding Information:
We would like to thank all members of the Owens lab for their input. We acknowledge Melissa Bevard, Coral Kasden, Angela Washington, and Mary McCanna for help with histology. We acknowledge Liming Yu and Rupa Tripathi for help with cell culture experiments. We acknowledge Gabriel Alencar for analysis of telemetry data. This work was supported by American Heart Association (AHA) Predoctoral Fellowship 15PRE25670040 (to D.L.H.), AHA Predoctoral Fellowship 16PRE3097006 (to M.R.K-G.), AHA Innovative Research Grant 17IRG33370017 (to O.A.C.), NIH Grants R01 HL082838, R01 Ey022063, and The Hartwell Foundation (to S.M.P.), NIH Grants 1R01 HL12635, 1R01 HL116455, 2R01 HL101200 (to B.H.A.), and NIH Grants R01 HL057353, R01 HL135018, and T32 HL007284 (to G.K.O.). This work was also supported by the Wagner Fellowship (M.R.K.-G.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The stem cell pluripotency factor Oct4 serves a critical protective role during atherosclerotic plaque development by promoting smooth muscle cell (SMC) investment. Here, we show using Myh11-CreER T2 lineage-tracing with inducible SMC and pericyte (SMC-P) knockout of Oct4 that Oct4 regulates perivascular cell migration and recruitment during angiogenesis. Knockout of Oct4 in perivascular cells significantly impairs perivascular cell migration, increases perivascular cell death, delays endothelial cell migration, and promotes vascular leakage following corneal angiogenic stimulus. Knockout of Oct4 in perivascular cells also impairs perfusion recovery and decreases angiogenesis following hindlimb ischemia. Transcriptomic analyses demonstrate that expression of the migratory gene Slit3 is reduced following loss of Oct4 in cultured SMCs, and in Oct4-deficient perivascular cells in ischemic hindlimb muscle. Together, these results provide evidence that Oct4 plays an essential role within perivascular cells in injury- and hypoxia-induced angiogenesis.
AB - The stem cell pluripotency factor Oct4 serves a critical protective role during atherosclerotic plaque development by promoting smooth muscle cell (SMC) investment. Here, we show using Myh11-CreER T2 lineage-tracing with inducible SMC and pericyte (SMC-P) knockout of Oct4 that Oct4 regulates perivascular cell migration and recruitment during angiogenesis. Knockout of Oct4 in perivascular cells significantly impairs perivascular cell migration, increases perivascular cell death, delays endothelial cell migration, and promotes vascular leakage following corneal angiogenic stimulus. Knockout of Oct4 in perivascular cells also impairs perfusion recovery and decreases angiogenesis following hindlimb ischemia. Transcriptomic analyses demonstrate that expression of the migratory gene Slit3 is reduced following loss of Oct4 in cultured SMCs, and in Oct4-deficient perivascular cells in ischemic hindlimb muscle. Together, these results provide evidence that Oct4 plays an essential role within perivascular cells in injury- and hypoxia-induced angiogenesis.
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U2 - 10.1038/s41467-019-08811-z
DO - 10.1038/s41467-019-08811-z
M3 - Article
C2 - 30814500
AN - SCOPUS:85062263741
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 967
ER -