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dc.contributor.authorBrzezinska, Paulinaen
dc.date.accessioned2019-11-20T19:55:39Z
dc.date.available2019-11-20T19:55:39Z
dc.identifier.urihttp://hdl.handle.net/1974/27457
dc.description.abstractVascular smooth muscle cells (VSMCs) are phenotypically plastic. Thus, while the VSMCs in healthy blood vessels are ‘contractile’ and control vascular tone, these cells can increase their synthetic, migratory and proliferative capacities in response to vessel injury. While largely adaptive, actions of “synthetic” VSMCs can promote arterial wall thickening and contribute to atherosclerosis and vessel stenosis. Currently, vessel stenosis is reversed by percutaneous coronary intervention (PCI) and the placement of drug eluting stents (DES) coated with pan-cellular anti-proliferative agents. Although these approaches are effective, in-stent restenosis and thrombosis remain problematic, in part due to limited re-endothelialization. Thus, DESs coated with drugs targeting specifically synthetic VSMCs, but not the endothelium, might limit these problems. Since the cyclic nucleotide phosphodiesterase, PDE1C, a dual cAMP/cGMP hydrolyzing PDE, is exclusively expressed by synthetic VSMCs and regulates their synthetic, migratory and proliferative actions, it may represent a valid synthetic VSMC specific therapeutic target. Store operated calcium entry (SOCE) allows refilling of depleted ER-Ca2+ stores in non-excited cells, including in synthetic VSMCs, and supports migration and proliferation of synthetic VSMCs. Herein, we identify a critical role for PDE1C in regulating the polarization of synthetic human arterial VSMCs (HASMCs) required for their migration and show how this PDE acts as a nexus allowing reciprocal regulation of the SOCE- and cAMP-signaling systems in these cells. Thus, we show that PDE1C localizes at lamellipodia formed by polarized/migrating HASMCs and coordinates a series of hyper-localized Ca2+ and cAMP signaling events within these structures which chronically antagonize their formation. Moreover, we show that these events are dependent on localized actions of the SOCE promoting machinery (i.e. Orai1/STIM1), a Ca2+-activated adenylyl cyclase (ADCY8), PKA and the A-kinase anchoring protein (AKAP79). Based on our findings, we suggest that inhibiting the actions of PDE1C may represent a valid novel therapeutic approach to decrease the burden associated with unregulated migration and proliferation of synthetic VSMCs.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectPDE1Cen
dc.subjectcAMP-signalingen
dc.subjectvascular smooth muscle cellsen
dc.subjectcalciumen
dc.subjectadenylyl cyclasesen
dc.subjectcyclic nucleotide phosphodiesterasesen
dc.titleCrosstalk Signaling Between cAMP and Calcium on the Leading Edge of Migrating Human Arterial Vascular Smooth Muscle Cellsen
dc.typethesisen
dc.description.degreePhDen
dc.contributor.supervisorMaurice, Donald H.en
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.embargo.termsChapter 3 has not been published and is currently in submissionen
dc.embargo.liftdate2024-11-20T16:28:04Z
dc.degree.grantorQueen's University at Kingstonen


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