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ROLE OF THE MECHANOSENSITIVE ION CHANNEL TRPV4 IN ANGIOGENESIS

Thoppil, Roslin Joseph
http://rave.ohiolink.edu/etdc/view?acc_num=kent1429536986

Abstract Details

2015, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Year and Degree 2015, PhD, Kent State University, College of Arts and Sciences/Department of Biomedical Sciences. Abstract THOPPIL, ROSLIN J.; Ph.D., May 2015 PHARMACOLOGY THE ROLE OF THE MECHANOSENSITIVE ION CHANNEL TRPV4 IN ANGIOGENESIS (158 pp) Director of Dissertation: Charles K. Thodeti Solid tumors require angiogenesis for growth and metastasis. Current anti-cancer therapies focus on mitogenic factors such as VEGF, which has clinically been met with limited success. However, angiogenesis is also regulated by mechanical forces which modulate endothelial cell (EC) responses to pro-angiogenic growth factors. We have previously shown that a mechanosensitive ion channel, TRPV4, is required for mechanical stretch-induced reorientation of normal EC (NEC). However, tumor derived-EC (TEC) failed to reorient in response to stretch as well as exhibited aberrant mechanosensitivity to substrate stiffness and abnormal angiogenesis in vitro. Based on these findings, we hypothesized that TRPV4 regulates tumor angiogenesis via modulation of EC mechanosensitivity. In specific aim 1, we investigated TRPV4-dependent signaling mechanisms in TEC mechanosensing and found TRPV4 expression and function was significantly diminished in TEC which may contribute to TEC aberrant mechanosensitivity and abnormal angiogenesis. TRPV4 overexpression or activation restored TEC mechanosensitivity and normalized angiogenesis by modulating Rho activity. Further, TRPV4 activation via small molecule activator GSK1016790A, in combination with anti-cancer drug Cisplatin, significantly reduced tumor growth in WT mice by inducing vessel maturation and vascular normalization. Since EC proliferation is a key angiogenic process, we examined in specific aim 2 if reduced TRPV4 levels contributes to TEC proliferation. In vitro studies revealed TEC proliferated at higher levels and express high basal ERK1/2 activity compared to NEC, which was significantly inhibited upon TRPV4 activation. Further, in WT mice treated with GSK1016790A, EC proliferation in tumors was significantly reduced. In specific aim 3, we explored the functional significance of TRPV4 signaling in physiological and pathological angiogenesis by employing WT and TRPV4KO mice. We found tumor angiogenesis and growth is enhanced in TRPV4KO mice compared to WT tumors. Further, aortic rings from TRPV4KO mice displayed increased vascular sprouting associated with enhanced EC proliferation, migration and angiogenesis in vitro that appeared to be mediated by high active ERK1/2 and Rho. Finally, pharmacological inhibition of Rho/ROCK pathway with Y-27632 in TRPV4KO mice, normalized abnormal tumor vasculature and reduced tumor growth in conjunction with Cisplatin. Together, our findings demonstrate TRPV4-dependent mechanotransduction in EC regulates angiogenesis via modulation of ERK1/2 and Rho/ROCK pathways.
Charles Thodeti (Advisor)
J. Gary Meszaros (Committee Member)
Priya Raman (Committee Member)
Moses Oyewumi (Committee Member)
Gail Fraizer (Committee Member)
158 p.
Biology; Biomedical Research; Molecular Biology; Pharmacology
TRPV4, angiogenesis, tumor endothelial cells, mechanosensitive ion channel

Recommended Citations

Citations

  • Thoppil, R. J. (2015). ROLE OF THE MECHANOSENSITIVE ION CHANNEL TRPV4 IN ANGIOGENESIS [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1429536986

    APA Style (7th edition)

  • Thoppil, Roslin. ROLE OF THE MECHANOSENSITIVE ION CHANNEL TRPV4 IN ANGIOGENESIS. 2015. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1429536986.

    MLA Style (8th edition)

  • Thoppil, Roslin. "ROLE OF THE MECHANOSENSITIVE ION CHANNEL TRPV4 IN ANGIOGENESIS." Doctoral dissertation, Kent State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=kent1429536986

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Kent State University and OhioLINK.