Endothelial and Smooth Muscle Cell Contribution to Vascular Pathology
Our laboratory is interested in how endothelial cells and smooth muscle cells develop during embryogenesis and maintain a mature, functional vasculature. In addition, changes in the function of vascular cells occur in vascular disease, and we are interested in the control of disease-related phenotypic alterations. Our current focus is the function of the Notch signaling pathway in these processes.
Role of Notch Signaling in Vascular Homeostasis and Remodeling
Most blood vessels in adult organisms have a very low rate of cellular proliferation. The endothelium is a primary mediator of homeostasis, forming a contact-inhibited monolayer with tight cellular junctions. DLL4 is highly expressed in arterial endothelial cells, and plays a critical role in maintaining endothelial cell quiescence. Circulating bone morphogenetic proteins (BMP), BMP9 and BMP10 are additional quiescence signals that promote homeostasis in endothelial cells. With an intact endothelium, the smooth muscle cells also remain in a quiescent, contractile state, with high expression of smooth muscle cell markers. Vascular smooth muscle cells in the homeostatic condition express primarily Notch3. Once the vasculature achieves its mature conformation and function, constant communication between vascular cells is required to maintain homeostasis, and to respond to external stimuli such as cytokines, hormones, changes in blood flow or shear stress, inflammation, and mechanical trauma. In particular, endothelial cell communication with vascular smooth muscle cells is mediated via Notch signaling on adjacent cells; however, unique mechanisms including paracrine signaling via exosomes are emerging.
Examples of Notch signaling in vascular activation include angiogenesis and arteriogenesis after ischemia, pulmonary hypertension, vascular occlusive diseases such as atherosclerosis, and arteriovenous malformations. Our goal is to understand pathological Notch signaling to understand how it impacts the progression of vascular disease.
Rostama B, Peterson SM, Vary CPH, Liaw L. Notch signal integration in the vasculature during remodeling. Vasc Pharmacol 2014, 63:97-104. NIHMSID #636614
Boucher JM, Harrington A, Rostama B, Lindner V, Liaw L. A receptor-specific function for Notch2 in mediating vascular smooth muscle cell growth arrest through p27kip1. Circ Res 2013, 113:975-985. PMCID: PMC3882755
Tang Y, Bai H, Urs S, Wang Z, Liaw L. Notch1 activation in embryonic VE-cadherin populations selectively blocks hematopoietic stem cell generation and fetal liver hematopoiesis. Transgenic Res 2013, 22:403-410. PMCID: PMC3594084 [available 4/1/2014]
Young K, Conley B, Romero D, Tweedie E, O’Neill C, Pinz I, Brogan L Lindner V, Liaw L, Vary CP. BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. Blood 2012, 120:4263-4273. PMCID:PMC3501721
Urs S, Henderson T, Le P, Rosen CJ, Liaw L. Tissue specific expression of Sprouty1 in mice protects against high fat diet induced fat accumulation, bone loss, and metabolic dysfunction. Br J Nutrition 2012, 6:1-9. NIHMSID #415296
Tang Y, Boucher JM, Liaw L. Histone deacetylase activity selectively regulates Notch-mediated smooth muscle differentiation in human vascular cells. J Amer Heart Assoc 2012, Jun;1(3):e000901, PMCID: PMC3487326
Urs S, Turner B, Tang Y, Rostama B, Small D, Liaw L. Effect of soluble Jagged-1- mediated inhibition of Notch signaling on proliferation and differentiation of an adipocyte progenitor cell model. Adipocyte 2012, 1:46-57
Boucher J, Gridley T, Liaw L. Molecular pathways of Notch signaling in vascular smooth muscle cells. Frontiers in Physiology, 2012, 3:81. PMCID: PMC3151075
Boucher JM, Peterson, SM, Urs S, Zhang C, Liaw L. The miR143/145 cluster is a novel transcriptional target of Jagged-1/Notch signaling in vascular smooth muscle cells. J Biol Chem 2011, 286:28312-28321. PMCID:PMC3151075
Tang Y, Yang X, Friesel RE, Vary CPH, Liaw L. Mechanisms of TGFbeta induced differentiation in human vascular smooth muscle cells. J Vasc Res 2011, 48:485-494. PMCID: PMC3169366
- Professor, Department of Medicine, Tufts University School of Medicine, Member Program in Cell, Molecular and Developmental Biology
- Director, Research Training Programs, Maine Medical Center Research Institute
- Professor, Tufts Clinical and Translational Science Institute
- Member, NHLBI Institutional Training Mechanism Review Committee, NIH
- Chair, External Advisory Committee, Maine INBRE
- Member, Advisory Board, Southern Maine Community College Biotechnology Program Advisory Board
- Member, American Heart Association