The vascular smooth muscle cell (SMC) alters its molecular and phenotypic characteristics during pathological vascular remodeling. Both Notch and TGF? signaling pathways promote a differentiated, contractile phenotype characteristic of mature SMC. However, mechanisms by which these pathways interact with each other are only beginning to be understood. Mutations in either pathway are causal for human cardiovascular disease, and therapies targeting these pathways are currently in clinical trials. Our laboratory discovered a regulatory interaction between Notch and Smad in SMC, which links Notch and TGF?/BMP/Smad signaling. Concomitant Notch and TGF? signaling leads to synergistic activation of phosphoSmad (pSmad) transcriptional activity and SMC marker expression. The goal of this project is to define mechanisms of integrative molecular signaling leading to SMC differentiation. This project utilizes molecular and biochemical signaling approaches in human primary vascular cells, and mouse transgenic models to study in vivo gene regulation and function. We propose the following hypotheses: 1) Jagged1 activation of Notch signaling in SMC transcriptionally represses the TGF? co-receptor, endoglin, via the canonical CBF-1 mediated pathway. 2) Coordinate Notch and TGF? signaling leads to synergistic activation of SMC contractile genes via interaction of CBF1- and pSmad- containing transcriptional complexes. 3) Activation of Notch in vivo in SMC prior to vascular injury will maintain the differentiated phenotype, leading to suppressed neointimal lesion formation and arteriogenesis.
Specific Aim 1 : Test the hypothesis that the TGF? co-receptor, endoglin, is transcriptionally regulated by Notch signaling in SMC.
This aim will utilize molecular assays in vitro and transgenic mouse models in vivo to characterize Notch regulation of endoglin expression and TGF? signaling in SMC.
Specific Aim 2 : Characterize the interaction of CBF1 and Smad transcriptional complexes on SMC contractile genes. We hypothesize that CBF1 and pSmad transcriptional complexes interact to transcriptionally regulate contractile genes including smooth muscle ?-actin (SM actin) and calponin1.
Specific Aim 3 : Determine how the regulation of endoglin and TGF? signaling by Notch affects pathological vascular remodeling. Established mouse transgenic strains will be evaluated in vascular disease models.
|Peterson, Sarah M; Turner, Jacqueline E; Harrington, Anne et al. (2018) Notch2 and Proteomic Signatures in Mouse Neointimal Lesion Formation. Arterioscler Thromb Vasc Biol 38:1576-1593|
|Yang, Xuehui; Gong, Yan; He, Qing et al. (2018) Loss of Spry1 attenuates vascular smooth muscle proliferation by impairing mitogen-mediated changes in cell cycle regulatory circuits. J Cell Biochem 119:3267-3279|
|Liaw, Lucy; Prudovsky, Igor; Koza, Robert A et al. (2016) Lipid Profiling of In Vitro Cell Models of Adipogenic Differentiation: Relationships With Mouse Adipose Tissues. J Cell Biochem 117:2182-93|
|Young, K; Krebs, L T; Tweedie, E et al. (2016) Endoglin is required in Pax3-derived cells for embryonic blood vessel formation. Dev Biol 409:95-105|
|Rostama, Bahman; Turner, Jacqueline E; Seavey, Guy T et al. (2015) DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1. Arterioscler Thromb Vasc Biol 35:2626-37|
|Young, Kira; Tweedie, Eric; Conley, Barbara et al. (2015) BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses. PLoS One 10:e0122892|
|Yang, Xuehui; Liaw, Lucy; Prudovsky, Igor et al. (2015) Fibroblast growth factor signaling in the vasculature. Curr Atheroscler Rep 17:509|
|Rostama, Bahman; Peterson, Sarah M; Vary, Calvin P H et al. (2014) Notch signal integration in the vasculature during remodeling. Vascul Pharmacol 63:97-104|
|Boucher, Joshua M; Harrington, Anne; Rostama, Bahman et al. (2013) A receptor-specific function for Notch2 in mediating vascular smooth muscle cell growth arrest through cyclin-dependent kinase inhibitor 1B. Circ Res 113:975-85|
|Marks, Peter C; Preda, Marilena; Henderson, Terry et al. (2013) Interactive 3D Analysis of Blood Vessel Trees and Collateral Vessel Volumes in Magnetic Resonance Angiograms in the Mouse Ischemic Hindlimb Model. Open Med Imaging J 7:19-27|
Showing the most recent 10 out of 11 publications