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Thesis - Ning Zhao040814 2.pdf (16.63 MB)

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Notch Signaling Guides Vascular Smooth Muscle Cell Function

Zhao, Ning
http://rave.ohiolink.edu/etdc/view?acc_num=osu1396890017

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Proper blood vessel formation and function is crucial for embryogenesis, wound healing, pregnancy and diseases. The interaction of endothelial cells and vascular smooth muscle cells/pericytes is critical for assembling and maintaining blood vessels. Previously, our lab and other groups showed that endothelial cells play an important role in governing vascular smooth muscle cell functions. To further investigate the signaling mechanisms that govern the interaction of vascular cells, we screened for genes and microRNAs whose expression was significantly altered by the endothelial cell-smooth muscle cell interaction. One of those altered genes was SYNDECAN-2, which encodes a heparin sulfate proteoglycan (HSPG) surface receptor. SYNDECAN-2 is known to be important for developmental processes including angiogenesis in vitro and in vivo, however the role of SYNDECAN-2 in vascular smooth muscle cells has not been identified. Our results show that endothelial cells induce mRNA expression of SYNDECAN-2 in smooth muscle cells by activating Notch receptor signaling. Both NOTCH2 and NOTCH3 contribute to the increased expression of SYNDECAN-2 and are themselves sufficient to promote its expression independent of endothelial cells. Syndecan family members serve as coreceptors for signaling molecules and interestingly, our data show that SYNDECAN-2 regulates Notch signaling and physically interacts with NOTCH3. Notch activity was attenuated in smooth muscle cells made deficient in SYNDECAN-2, and this specifically prevented the expression of differentiation marker smooth muscle a-actin (ACTA2). These results show a novel mechanism in which Notch receptors control their own activity by inducing the expression of SYNDECAN-2 that then acts to propagate Notch signaling by direct receptor interaction. miR-145 is considered as a smooth muscle specific microRNA, and has been implicated in vascular smooth muscle cell differentiation, but its mechanisms of action and downstream targets have not been fully defined. Our lab previously showed that endothelial cells promote smooth muscle differentiation, and here we show that the miR-143/145 gene cluster is induced in smooth muscle cells by coculture with endothelial cells. Endothelial cell-induced expression of miR-143/145 is augmented by Notch signaling and accordingly expression is reduced in Notch receptor-deficient cells. To further define the function of miR-145 in smooth muscle cells, we screened putative target genes to identify over represented signaling pathways. Our results revealed that the TGFß pathway has a significantly high number of miR-145 target genes, and we show that TGFß receptor II (TGFBR2) is a direct target of miR-145. Extracellular matrix (ECM) genes, which are regulated by TGFBR2, were attenuated by miR-145 overexpression, and miR-145 mutant mice exhibit an increase in ECM synthesis. Furthermore, activation of TGFß signaling via angiotensin II infusion revealed a pronounced fibrotic response in the absence of miR-145. These data demonstrate a specific role for miR-145 in the regulation of matrix gene expression in smooth muscle cells, and suggest that miR-145 acts to suppress TGFß-dependent ECM accumulation and fibrosis, while promoting TGFß-induced smooth muscle cell differentiation. Our findings offer evidence to explain how TGFß signaling exhibits distinct downstream actions via its regulation by a specific microRNA.
Brenda Lilly (Advisor)
154 p.
Developmental Biology; Molecular Biology
Notch; vascular smooth muscle cell; SYNDECAN-2; microRNA; TGFbeta; matrix synthesis

Recommended Citations

Citations

  • Zhao, N. (2014). Notch Signaling Guides Vascular Smooth Muscle Cell Function [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1396890017

    APA Style (7th edition)

  • Zhao, Ning. Notch Signaling Guides Vascular Smooth Muscle Cell Function. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1396890017.

    MLA Style (8th edition)

  • Zhao, Ning. "Notch Signaling Guides Vascular Smooth Muscle Cell Function." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1396890017

    Chicago Manual of Style (17th edition)

osu1396890017
276
© 2014, some rights reserved.Creative Commons License Notch Signaling Guides Vascular Smooth Muscle Cell Function by Ning Zhao is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.