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Profilin-1 as a Regulator of Vascular Endothelial-Immune Cell Crosstalk

Gondringer, Abigail (2024) Profilin-1 as a Regulator of Vascular Endothelial-Immune Cell Crosstalk. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Actin cytoskeleton plays a key role in vascular endothelial cell (EC) integrity. Cytoskeletal changes promote EC dysfunction and vascular infiltration of immune cells during inflammation. The overall goal of this dissertation is to study the role of Profilin1 (Pfn1), an actin monomer binding-protein and an important regulator of actin cytoskeletal dynamics, in vascular EC-immune cell crosstalk. To this end, we generated an inducible vascular-EC-specific Pfn1 knockout mouse model. We demonstrated that triggering widespread deletion of vascular EC Pfn1 in adult mice leads to severe health complications presenting overt pathologies (EC death, infarct, and fibrosis) in major organ systems and evidence for inflammatory infiltrates, ultimately compromising the survival of animals within 3 weeks of gene ablation. Mice deficient in EC Pfn1 exhibit selective bias towards the pro-inflammatory myeloid-derived population of immune cells, a finding further supported by systemic elevation of pro-inflammatory cytokines. Triggering Pfn1 depletion not only upregulates pro-inflammatory cytokine/chemokine gene expression in EC (a finding consistent with elevated STAT1/interferon signaling) but also potentiates the paracrine effect of EC on pro-inflammatory gene expression in macrophages. Collectively, these findings for the first time demonstrate a prominent immunological consequence of loss of EC Pfn1, and an indispensable role of EC Pfn1 in mammalian survival unlike tolerable phenotypes of Pfn1 loss in other differentiated cell types. Finally, we examine the impact of haplo-insufficiency of EC Pfn1 in a vascular disease context utilizing a mouse model of atherosclerosis, where reduced cytotoxic T cells and elevated B cell populations, paired with reduced pro-atherogenic cytokines CXCL10 and IL7, offer some support for partial EC Pfn1 deletion in modulating chronic inflammation.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gondringer, Abigailaea55@pitt.eduaea55@pitt.edu0000-0002-3447-0612
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRoy, Parthapar19@pitt.edu
Committee MemberDutta, Parthaduttapa@pitt.edu
Committee MemberShroff, Sanjeevsshroff@pitt.edu
Committee MemberSims-Lucas, Sundersunder.sims-lucas@chp.edu
Committee MemberStorkus, Walterstorkuswj@upmc.edu
Date: 11 January 2024
Date Type: Publication
Defense Date: 9 November 2023
Approval Date: 11 January 2024
Submission Date: 25 October 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 128
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: actin, cytoskeleton, Profilin-1, Pfn1, atherosclerosis, inflammation, cardiovascular disease, mouse model
Date Deposited: 11 Jan 2024 19:37
Last Modified: 11 Jan 2024 19:37
URI: http://d-scholarship.pitt.edu/id/eprint/45436

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