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Novel Approaches to Modulate Endothelial Cell Migration and Angiogenesis

Gau, David (2018) Novel Approaches to Modulate Endothelial Cell Migration and Angiogenesis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Angiogenesis, the process of neovascularization from pre-existing vasculature, is fundamental to development and tissue repair. However, aberrant angiogenesis exacerbates progression of a number of diseases including but not limited to cancer and diabetic retinopathy. Endothelial cell (EC) migration, a key event for angiogenesis, is a highly regulated process that critically relies on the dynamic remodeling of the actin cytoskeleton via orchestrated actions of various actin-binding proteins. An important aspect of the dynamic remodeling of the actin cytoskeleton, cell migration, and angiogenesis is stimulus-induced regulation of de novo synthesis of many important molecular components of the actin cytoskeleton by MKL (Megakaryoblastic Leukemia)–SRF (Serum-Response Factor) transcriptional machineries. Given the previous genetic evidence for the importance of MKL/SRF signaling in EC migration and angiogenesis, we first set out to explore whether angiogenesis is susceptible to small molecule-mediated inhibition of the MKL/SRF pathway. Our studies showed that CCG-1423, a small molecule inhibitor of MKL, causes a prominent defect in EC migration and angiogenesis in vitro, ex vivo, and in vivo. Inhibition of MKL led to prominent depletion of actin-binding protein Profilin-1 (Pfn1), an important molecular player of membrane protrusion and EC migration/angiogenesis, but through an unconventional indirect mechanism that involves a cellular externalization control [Angiogenesis (2017) 20(4):663-672; J. Biol Chem. (2017) 292(28):11777-11791]. Next, guided by computational-based rational design, we identified the first-generation small molecule inhibitors of the Pfn1:actin interaction, and further demonstrated the ability of these small molecules to inhibit EC migration, proliferation, and angiogenesis in vitro and ex vivo [J Biol Chem (2017) Dec 27, epub]. Finally, to gain new insights on the regulation of Pfn1, we identified and explored the consequence of novel phosphorylation event which caused insoluble aggregation of Pfn1 and actin molecules [PLoS One (2016) 26;11(5):e0156313].


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gau, Daviddmg40@pitt.edudmg40@pitt.edu0000-0002-3079-3692
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRoy, Parthapar19@pitt.edupar19
Committee MemberWells, Alanwellsa@upmc.edu
Committee MemberBanerjee, Ipsitaipb1@pitt.eduipb1
Committee MemberHallows, Kennethhallows@usc.edu
Date: 11 June 2018
Date Type: Publication
Defense Date: 28 February 2018
Approval Date: 11 June 2018
Submission Date: 27 March 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 176
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: MKL, profilin, CCG-1423, angiogenesis, cell migration
Date Deposited: 11 Jun 2018 19:54
Last Modified: 11 Jun 2018 19:54
URI: http://d-scholarship.pitt.edu/id/eprint/33991

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