title: Endothelial cells downregulate apolipoprotein D expression in mural cells through paracrine secretion and Notch signaling.
abstract: Endothelial and mural cell interactions are vitally important for proper formation and function of blood vessels. These two cell types communicate to regulate multiple aspects of vessel function. In studying genes regulated by this interaction, we identified apolipoprotein D (APOD) as one gene that is downregulated in mural cells by coculture with endothelial cells. APOD is a secreted glycoprotein that has been implicated in governing stress response, lipid metabolism, and aging. Moreover, APOD is known to regulate smooth muscle cells and is found in abundance within atherosclerotic lesions. Our data show that the regulation of APOD in mural cells is bimodal. Paracrine secretion by endothelial cells causes partial downregulation of APOD expression. Additionally, cell contact-dependent Notch signaling plays a role. NOTCH3 on mural cells promotes the downregulation of APOD, possibly through interaction with the JAGGED-1 ligand on endothelial cells. Our results show that NOTCH3 contributes to the downregulation of APOD and by itself is sufficient to attenuate APOD transcript expression. In examining the consequence of decreased APOD expression in mural cells, we show that APOD negatively regulates cell adhesion. APOD attenuates adhesion by reducing focal contacts; however, it has no effect on stress fiber formation. These data reveal a novel mechanism in which endothelial cells control neighboring mural cells through the downregulation of APOD, which, in turn, influences mural cell function by modulating adhesion.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Mohanasundari
authors.initials: M
authors.lastname: Pajaniappan
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Glober
authors.forename: Simone
authors.initials: S
authors.lastname: Kennard
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Brenda
authors.initials: B
authors.lastname: Lilly
mesh_terms: D000704:Analysis of Variance; D053399:Apolipoproteins D / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism; D017930:Genes, Reporter; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D019899:Paracrine Communication; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014162:Transfection
chemical_list: C024328:APOD protein, human; D053399:Apolipoproteins D; D002135:Calcium-Binding Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins