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The Roles of the Notch2 and Notch3 Receptors in Vascular Smooth Muscle Cells

Baeten, Jeremy T
http://rave.ohiolink.edu/etdc/view?acc_num=osu1480513055823902

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
The Notch signaling pathway has long been intricately linked with the development and function of the vasculature. In vascular smooth muscle cells (VSMCs), Notch signaling has a great influence on phenotype and is a strong promoter of differentiation and expression of contractile genes necessary to produce a functional vessel wall. However, the role of Notch signaling in VSMC proliferation and survival is less well defined, and some cases contradictory reports are given. Also, the contributions of each individual Notch receptor have not been clearly described. Thus, to better understand Notch signaling in VSMC phenotype, we investigated the specific roles of the predominant Notch receptors in VSMCs as they relate to differentiation, proliferation, and survival. We found that Notch3 promotes Platelet-Derived Growth Factor (PDGF)-induced proliferation in VSMCs, while Notch2 inhibits it. We also found that Notch3 was able to promote cell survival in response to apoptosis cues, while Notch2 had no discernible effect. Interestingly, we also found the expression of Notch2 and Notch3 were changed in response to proliferation and apoptosis inducers. Notch2 mRNA was significantly decreased after PDGF-BB treatment, a proliferation inducer, and Notch3 protein was degraded rapidly in response to induction of apoptosis. Additionally, we demonstrated that Notch3’s induction of cell survival genes required MEK/ERK signaling and Notch3 was capable of increasing levels of phosphorylated ERK. Altogether, these findings demonstrate that Notch2 and Notch3 have unique functions in regulating VSMC phenotype. In a mouse model devoid of Notch2 and Notch3 in smooth muscle cells, we were able to show that Notch2 and Notch3 are required for normal closure of the ductus arteriosus. Animals without Notch2 in VSMCs presented with patent ductus arteriosus with increasing incidence combined with the loss of Notch3. These mice died within one day of birth and also presented with aortic dilation. These phenotypes wee correlated with a significant loss of the smooth muscle contractile genes MYH11 and ACTA2, and it has been previously reported that defects in contractile differentiation can produce the PDA phenotype. This suggests that the Notch2 and Notch3 share an overlapping role in promoting VSMC differentiation. The Notch-regulated microRNA 145 has been strongly implicated in VSMC differentiation and also recently shown to regulate cardiovascular fibrosis. In order to better understand these connections to differentiation and fibrosis, we created and characterized a transgenic mouse for conditional expression of miR145, miR145TG. We were able to select a line that faithfully expresses the transgene and produces mature miR145 transcript. This model will allow for further investigation into miR145’s roles in promoting VSMC differentiation and mediating fibrosis.
Brenda Lilly, PhD (Advisor)
Joy Lincoln, PhD (Committee Member)
Andrea Doseff, PhD (Committee Member)
Aaron Trask, PhD (Committee Member)
175 p.
Biomedical Research; Cellular Biology; Developmental Biology; Molecular Biology
Notch signaling; vascular smooth muscle cells; PDA; VSMC differentiation; miR145

Recommended Citations

Citations

  • Baeten, J. T. (2016). The Roles of the Notch2 and Notch3 Receptors in Vascular Smooth Muscle Cells [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480513055823902

    APA Style (7th edition)

  • Baeten, Jeremy. The Roles of the Notch2 and Notch3 Receptors in Vascular Smooth Muscle Cells. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1480513055823902.

    MLA Style (8th edition)

  • Baeten, Jeremy. "The Roles of the Notch2 and Notch3 Receptors in Vascular Smooth Muscle Cells." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480513055823902

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.