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The Regulation of Vascular Smooth Muscle Cell Phenotype and Function by Nitrite and Mitofusin-1

Reyes, Christopher (2020) The Regulation of Vascular Smooth Muscle Cell Phenotype and Function by Nitrite and Mitofusin-1. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Restenosis is a clinical complication affecting 20% of people who undergo balloon angioplasty to treat atherosclerotic plaques. Restenosis is driven by vascular smooth muscle cell (VSMC) dysfunction. Physiologically, VSMC are the primary mediators of vessel tone, which respond to molecular and biomechanical cues to modulate blood flow. During restenosis, the endothelium is disrupted resulting in a local inflammatory response; consequently, VSMC transition from a highly-specialized contractile cell to a proliferative, synthetic phenotype. This results in increased migration to the intimal layer of the vessel where VSMC aberrantly proliferate (neointimal hyperplasia), decreasing lumen diameter and potentiating future infarct. Nitrite, an endogenously generated oxidation product of nitric oxide and regulator of mitochondrial function, has recently been suggested to attenuate restenosis after vascular injury. However, the mechanisms by which nitrite modulates VSMC proliferation and phenotypic switching remains unknown. Herein, we demonstrate nitrite has opposing effects on cellular proliferation versus phenotypic switching. First, we show that nitrite inhibits growth factor stimulated-proliferation of rat aortic smooth muscle cells (RASMC). This effect is dependent on inhibition of E3 ubiquitin ligase March5, which leads to upregulation of mitochondrial dynamics protein mitofusin-1 (Mfn1) and subsequent cell cycle arrest. In contrast, our data reveal that nitrite promotes RASMC migration and decreases contractile gene expression, consistent with switching from contractile to synthetic phenotype. Notably, nitrite’s effects on phenotypic switching were independent of Mfn1. To further investigate the interaction between nitrite and Mfn1 and its role in VSMC function in vivo, a smooth muscle cell-specific Mfn1 knockout (KO) mouse was generated. In a carotid artery ligation model to mimic restenosis after balloon angioplasty, Mfn1 KO mice exhibited significantly increased neointimal hyperplasia in response to injury compared to control animals. Oral administration of nitrite attenuated neointimal hyperplasia in Mfn1 KO mice but not wildtype mice. In sum, these data demonstrate that nitrite is a regulator of VSMC function both through the modulation of Mfn1 (for proliferation) and independent of this protein (for phenotypic switching). The implications of these data for nitrite as a potential therapeutic agent for neointimal hyperplasia as well as Mfn1 as a putative therapeutic target will be discussed.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Reyes, Christophercrreyes14@gmail.comcrr63@pitt.edu0000-0002-6735-7624
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorShiva, Srutisss43@pitt.edusss43@pitt.edu0000-0003-3535-2113
Committee MemberShroff, Sanjeevsshroff@pitt.edusshroff@pitt.edu0000-0003-1868-3826
Committee MemberRoy, Parthapar19@pitt.edupar19@pitt.edu0000-0002-4946-8531
Committee MemberSundd, Prithuprs51@pitt.eduprs51@pitt.edu0000-0001-7568-5719
Committee MemberStraub, Adamastraub@pitt.eduastraub@pitt.edu0000-0003-0542-9466
Date: 28 September 2020
Date Type: Publication
Defense Date: 8 July 2020
Approval Date: 28 September 2020
Submission Date: 25 June 2020
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 183
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: nitrite; mitofusin-1; mitochondria; smooth muscle; restenosis
Date Deposited: 28 Sep 2020 18:20
Last Modified: 28 Sep 2020 18:20
URI: http://d-scholarship.pitt.edu/id/eprint/39273

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