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THE ROLE OF CANONICAL TRANSIENT RECEPTOR POTENTIAL CHANNEL SUBTYPE-6 IN PHENOTYPIC MODULATION OF VASCULAR SMOOTH MUSCLE CELLS AND ARTERIAL HEALING AFTER VASCULAR INTERVENTION

Smith, Andrew Hart
http://rave.ohiolink.edu/etdc/view?acc_num=case160710077734737

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Mechanism-based therapies that mitigate phenotypic modulation of vascular smooth muscle cells (SMC) represent appealing targets to improve outcomes of vascular intervention by limiting restenosis. Canonical transient receptor potential channel subtype-6 (TRPC6) is upregulated in arterial segments following balloon angioplasty, though its role in the pathogenesis of neointimal hyperplasia (IH) is unclear. We hypothesized that TRPC6 is required for maintenance of myocardin expression and stabilizes the contractile phenotype in SMC to reduce stenosis in a model of arterial intervention. In this study, histologic evaluation of TRPC6-/- common carotid arteries (CCA) demonstrated subtle structural deficits, including luminal dilation, medial thinning and decreased elastin lamella compared to WT CCA. These structural deficits were associated with reduced myocardin expression in TRPC6-/- CCA homogenates. To assess the effects of TRPC6 on arterial healing after vascular intervention, WT and TRPC6-/- mice were subjected to carotid wire injury. Evaluation at 28 days post injury demonstrated that luminal stenosis, negative arterial remodeling and neointimal hyperplasia were accentuated in TRPC6-/- mice compared to WT mice. TRPC6-/- carotid arteries showed increased medial and neointimal cell proliferation after injury. Immunohistochemistry suggested persistent attenuation of contractile biomarker expression in the media of TRPC6-/- CCA but complete restoration of contractile biomarker expression in in the media of WT CCA 28 days after wire injury. In vitro, cultured primary aortic TRPC6-/- SMC showed decreased expression of SM22, MYH11 and myocardin. Loss of contractile biomarker expression in TRPC6-/- SMC was accompanied by the emergence of IH-related behaviors including enhanced proliferation and migration. Acute siRNA-mediated knockdown of TRPC6 in immortalized arterial SMC was sufficient to induce myocardin downregulation and phenotypic modulation. In total, these results suggest that TRPC6 plays a protective and deterministic role in maintenance of the SMC contractile phenotype, and that absence of TRPC6 promotes IH and luminal stenosis following vascular intervention.
Linda Graham, MD (Advisor)
Jonathan Smith, PhD (Committee Chair)
Christine Moravec, PhD (Committee Member)
Mitchell Olman, MD (Committee Member)
Edward Maytin, MD PhD (Committee Member)
134 p.
Medicine; Molecular Biology; Surgery
Molecular medicine, vascular surgery, vascular smooth muscle cells, neointimal hyperplasia, canonical transient receptor potential channel subtype-6, myocardin

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Citations

  • Smith, A. H. (2021). THE ROLE OF CANONICAL TRANSIENT RECEPTOR POTENTIAL CHANNEL SUBTYPE-6 IN PHENOTYPIC MODULATION OF VASCULAR SMOOTH MUSCLE CELLS AND ARTERIAL HEALING AFTER VASCULAR INTERVENTION [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case160710077734737

    APA Style (7th edition)

  • Smith, Andrew. THE ROLE OF CANONICAL TRANSIENT RECEPTOR POTENTIAL CHANNEL SUBTYPE-6 IN PHENOTYPIC MODULATION OF VASCULAR SMOOTH MUSCLE CELLS AND ARTERIAL HEALING AFTER VASCULAR INTERVENTION . 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case160710077734737.

    MLA Style (8th edition)

  • Smith, Andrew. "THE ROLE OF CANONICAL TRANSIENT RECEPTOR POTENTIAL CHANNEL SUBTYPE-6 IN PHENOTYPIC MODULATION OF VASCULAR SMOOTH MUSCLE CELLS AND ARTERIAL HEALING AFTER VASCULAR INTERVENTION ." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case160710077734737

    Chicago Manual of Style (17th edition)

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© 2021, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12