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Thesis_Sankha_Ghosh.pdf (6.91 MB)

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REGULATION OF ACTIVATION PHASE OF ANGIOGENESIS BY TRANCRIPTION FACTORS ETS1 AND ETS2

Ghosh, Sankha
http://rave.ohiolink.edu/etdc/view?acc_num=osu1409052955

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Vascular remodeling is a necessary process not only for embryonic development but also for specific physiological and pathological conditions in adult. Several growth factors are required at specific stages in order for the vascular development to occur. Angiogenesis also involves complex crosstalk between several endothelial cell (EC) processes including cell cycle, cell survival and migration. Signaling pathways, stimulated by the growth factors and communication between endothelial cells and extra cellular matrix (ECM), coordinate these processes. Deregulation of any of the factors or pathways can lead to severe defects in vessel formation. Transcription factors ETS1 and ETS2 are required for EC functions necessary for embryonic angiogenesis. EC specific deletion of ETS2 with conventional deletion of ETS1 results in defective vascular branching. Additionally, the double mutant embryos are embryonic lethal. Owing to this lethal nature, the specific gene targets of these factors are yet to be identified. In the current study, we elucidate the effect of endothelial cell specific deletion of Ets1 and Ets2 on angiogenesis and characterize the downstream regulatory pathways. Inducible Cre-loxp technology was used to specifically delete both Ets1 and Ets2 in endothelial cells after birth. Deletion of Ets1 and Ets2, when restricted to endothelial cells in new born mice (P1-P3), reduced retinal angiogenesis. Similarly, EC infiltration and invasion into matrigel plugs subsided when matrigel admixed with mouse mammary tumor cells was injected into adult mice with inactivated Ets1 and Ets2 specifically in ECs. Gene expression array performed on RNA, isolated from cultured aortic endothelial cells, comparing the double knockout cells with controls revealed reduced expression of key cell cycle and cell survival regulators in double mutant cells. In addition, both these factors were found to occupy the enhancer regions of the target genes indicating these factors directly regulate expression of the target genes. Recruitment of coactivators CBP/p300 was diminished in the absence of ETS1 and ETS2. Deletion of Ets1 and Ets2 in cultured aortic EC resulted in altered cell cycle phases with a G2/M phase arrest and increased sensitivity to apoptosis in vitro. These results demonstrate that deletion of Ets1 and Ets2 in endothelial cells inhibits angiogenesis by blocking cell cycle progression and decreasing cell survival.
Michael Ostrowski (Advisor)
Jeffrey Parvin (Committee Member)
Denis Guttridge (Committee Member)
Qianben Wang (Committee Member)
185 p.
Developmental Biology; Genetics; Molecular Biology

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Citations

  • Ghosh, S. (2014). REGULATION OF ACTIVATION PHASE OF ANGIOGENESIS BY TRANCRIPTION FACTORS ETS1 AND ETS2 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1409052955

    APA Style (7th edition)

  • Ghosh, Sankha. REGULATION OF ACTIVATION PHASE OF ANGIOGENESIS BY TRANCRIPTION FACTORS ETS1 AND ETS2. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1409052955.

    MLA Style (8th edition)

  • Ghosh, Sankha. "REGULATION OF ACTIVATION PHASE OF ANGIOGENESIS BY TRANCRIPTION FACTORS ETS1 AND ETS2." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1409052955

    Chicago Manual of Style (17th edition)

osu1409052955
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