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Transcriptional Regulation of Developmental and Tumor-Induced Angiogenesis by Etv2 and Fli1b

Craig, Michael P
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427982504

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
The first embryonic vessels form de novo from endothelial progenitors by vasculogenesis, and further expansion of the vascular bed occurs by angiogenic sprouting. Angiogenesis remains important in wound healing, estrous and tumor vascularization, thus highlighting the need for strategies designed to harness angiogenic potential. Many of the molecular cues required for the formation, patterning and maintenance of the vertebrate vascular bed have been identified, but the signaling cascades underlying these phenomena are poorly understood. This dissertation explores the overlapping functional roles played by the vascular-specific ETS transcription factors during embryonic development and tumor-induced angiogenesis. The ETS factors Etv2/ER71, Fli1a and Fli1b are specifically expressed in the vascular endothelium during early development. Previous studies have clearly shown that etv2 is required for establishing the endothelial lineage, but morpholino (MO) knockdown of fli1a and fli1b has thus far failed to elucidate clear roles for either Fli1a or Fli1b. Etv2 mutants die during embryonic development due to failed vasculogenesis, but nonetheless exhibit a partial angiogenic vessel recovery potentially mediated by the other vascular ETS factors. In this dissertation, we utilized recently available Fli1a and Fli1b gene-trap mutant lines in combination with etv2 MO knockdown in order to more fully elucidate the individual and combinatorial roles of each. Fli1a or Fli1b homozygous mutant zebrafish embryos developed normally with no apparent vascular defects, yet embryos deficient in both Etv2 and Fli1b (but not Etv2 and Fli1a) failed to form angiogenic sprouts due to increased apoptotic loss of vascular endothelial cells throughout the axial vasculature suggesting that Etv2 and Fli1b function in a partially redundant manner. Temporal inhibition of Etv2 function using photoactivatable morpholinos further suggested that Etv2 and Fli1b function together to support sprouting angiogenesis. Overexpression, knockdown, RNA sequencing (RNA-Seq), and chromatin immunoprecipitation (ChIP) collectively indicate that Etv2 and Fli1b induce a similar set of downstream transcriptional targets. Additionally, we utilized a melanoma xenograft model to show that Etv2 has a previously unrecognized critical function during sprouting and tumor-induced angiogenesis, and may thus represent a novel therapeutic target for enhancing angiogenesis during wound healing and for blocking tumor-induced angiogenesis. Collectively, our data suggests that therapeutic targeting of multiple vascular ETS factors may be beneficial in controlling angiogenesis.
Saulius Sumanas, Ph.D. (Committee Chair)
Walter Jones, Ph.D. (Committee Member)
Marshall Montrose, Ph.D. (Committee Member)
Gary Edward Shull, Ph.D. (Committee Member)
Joshua Waxman, Ph.D. (Committee Member)
Yana Zavros, Ph.D. (Committee Member)
172 p.
Developmental Biology
angiogenesis; vasculogenesis; melanoma; zebrafish; etv2; fli1b

Recommended Citations

Citations

  • Craig, M. P. (2015). Transcriptional Regulation of Developmental and Tumor-Induced Angiogenesis by Etv2 and Fli1b [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427982504

    APA Style (7th edition)

  • Craig, Michael. Transcriptional Regulation of Developmental and Tumor-Induced Angiogenesis by Etv2 and Fli1b. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427982504.

    MLA Style (8th edition)

  • Craig, Michael. "Transcriptional Regulation of Developmental and Tumor-Induced Angiogenesis by Etv2 and Fli1b." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427982504

    Chicago Manual of Style (17th edition)

ucin1427982504
467
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This open access ETD is published by University of Cincinnati and OhioLINK.