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TRPV4 Mechanotransduction in Vascular Growth and Integrity

Cappelli, Holly
http://rave.ohiolink.edu/etdc/view?acc_num=kent1487764322127302

Abstract Details

2017, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Angiogenesis is a determining pathophysiological factor for more than 70 major health conditions, including proliferative vascular diseases, arthritis, heart disease, and cancer. Many existing therapies of pathological angiogenesis focus on the influences of soluble growth factors. However, mechanical forces generated by hemodynamics also play a crucial role in this process. In recent years, TRPV4 has become a well-established mechanosensitive ion channel involved in the endothelium and in vitro studies from our lab have revealed the importance of TRPV4-mediated endothelial mechanosensing in angiogenesis. Here, we hypothesized that TRPV4 is a critical regulator of angiogenesis as well as vascular integrity and that deregulation of TRPV4 signaling can lead to pathological angiogenesis. The first aim of this dissertation was to determine if TRPV4-dependent mechanotransduction mediates angiogenesis and vessel integrity in vivo. Using in vivo Matrigel plugs of varying stiffness, we found TRPV4KO mice exhibited vessel malformations, characterized by increased vascular growth and vessel area, in response to changes in substrate stiffness. We also revealed a role for TRPV4 in vessel maturation by exposing a connection between TRPV4 and VE-cadherin, demonstrating that when TRPV4 expression is deficient or absent, VE-cadherin accumulation at cell-cell contacts is reduced. Further, absence of TRPV4 resulted in decreased VE-cadherin and pericyte coverage, increased permeability, and metastasis in a model of tumor angiogenesis. To determine if these pathological abnormalities exist in other angiogenic models, the second aim of this dissertation was to determine the functional significance of TRPV4 in pathological retinal angiogenesis. Our in vitro studies confirmed that TRPV4 is expressed, functional, and mechanosensitive in retinal endothelial cells. Importantly, we found that the absence of TRPV4 did not affect developmental vascularization of the retina in vivo. Thus, we employed a mouse model of oxygen-induced retinopathy, which mimics retinopathy of prematurity, in WT and TRPV4KO mouse pups and found that TRPV4KO mice exhibited increased vaso-obliteration and neovascularization leading to unproductive angiogenesis. Assessment of vascular integrity demonstrated that absence of TRPV4 resulted in poor pericyte coverage in the P17 OIR retina in vivo and decreased VE-cadherin localization at cell-cell contacts in vitro. Overall, these results identify TRPV4 as a mechanosensor that regulates vascular integrity, directly or indirectly mediating VE-cadherin stability in both physiological and pathological angiogenesis.
Charles Thodeti, Ph.D. (Advisor)
William Chilian, Ph.D. (Committee Member)
Liya Yin, M.D.,Ph.D. (Committee Member)
Moses Oyewumi, Ph.D. (Committee Member)
Derek Damron, Ph.D. (Committee Member)
147 p.
Biology; Biomedical Research; Physiology
TRPV4; mechanosensitive ion channel; angiogenesis; vascular integrity; endothelial cells; retina; retinal angiogenesis; tumor angiogenesis; oxygen-induced retinopathy

Recommended Citations

Citations

  • Cappelli, H. (2017). TRPV4 Mechanotransduction in Vascular Growth and Integrity [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1487764322127302

    APA Style (7th edition)

  • Cappelli, Holly. TRPV4 Mechanotransduction in Vascular Growth and Integrity. 2017. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1487764322127302.

    MLA Style (8th edition)

  • Cappelli, Holly. "TRPV4 Mechanotransduction in Vascular Growth and Integrity." Doctoral dissertation, Kent State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=kent1487764322127302

    Chicago Manual of Style (17th edition)

kent1487764322127302
236
© 2017, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.