Arterial smooth muscle cells (SMCs) mediate arterial remodeling and repair. SMCs are phenotypically plastic and can transition to proliferative, migratory """"""""synthetic"""""""" SMCs that modulate intimal hyperplasia and stability of atherosclerotic plaques, and SMC chondro- osseous phenotypic transition promotes artery calcification. Our central hypothesis is that the multifunctional protein transglutaminase 2 (TG2), a known mediator of wound repair and tissue fibrosis, regulates both atherosclerotic lesion calcification and progression. Expression of TG2 is increased in atherosclerotic lesions. Activated cells release TG2, and TG2 covalently crosslinks numerous extracellular matrix substrate proteins via transamidation. TG2 also has reciprocally regulated TG and GTP binding/GTPase activities, and is an integrin co-receptor for fibronectin. TG2 modulates SMC adhesion, migration, differentiation and function. Resistance artery remodeling induced by chronic vasoconstriction is TG2-dependent. Our Preliminary Studies reveal that TG2 regulates chondro-osseous differentiation and calcification in cultured chondrocytes and aortic SMCs. TG2 also regulates SMC expression of the calcification inhibitor and pro-atherogenic phosphoprotein osteopontin, a marker of the transition of SMCs from contractile to synthetic differentiation. Bone marrow-specific TG2 expression limits atherosclerotic lesion size in LDL receptor knockout bone marrow recipients and TG2 appears to drive mouse aortic valve calcification. We will test the linked hypotheses that extracellular TG2, by modifying the extracellular matrix, constitutively restrains cultured aortic SMC transition from contractile to synthetic differentiation but that excess TG2 drives phenotypic SMC transition to chondro-osseous calcifying cells in vitro. We also will test the hypothesis that TG2 limits atherosclerotic plaque vulnerability while concurrently promoting atherosclerotic intimal lesion calcification in vivo, studying apoE TG2 double knockout mice. Completion of these studies will delineate the potential for modulation of arterial TG2 as a therapy to suppress artery calcification or atherosclerotic lesion progression. ? ? ?
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