title: Increased tissue transglutaminase activity contributes to central vascular stiffness in eNOS knockout mice.
abstract: Nitric oxide (NO) can modulate arterial stiffness by regulating both functional and structural changes in the arterial wall. Tissue transglutaminase (TG2) has been shown to contribute to increased central aortic stiffness by catalyzing the cross-linking of matrix proteins. NO S-nitrosylates and constrains TG2 to the cytosolic compartment and thereby holds its cross-linking function latent. In the present study, the role of endothelial NO synthase (eNOS)-derived NO in regulating TG2 function was studied using eNOS knockout mice. Matrix-associated TG2 and TG2 cross-linking function were higher, whereas TG2 S-nitrosylation was lower in the eNOS(-/-) compared with wild-type (WT) mice. Pulse-wave velocity (PWV) and blood pressure measured noninvasively were elevated in the eNOS(-/-) compared with WT mice. Intact aortas and decellularized aortic tissue scaffolds of eNOS(-/-) mice were significantly stiffer, as determined by tensile testing. The carotid arteries of the eNOS(-/-) mice were also stiffer, as determined by pressure-dimension analysis. Invasive methods to determine the PWV-mean arterial pressure relationship showed that PWV in eNOS(-/-) and WT diverge at higher mean arterial pressure. Thus eNOS-derived NO regulates TG2 localization and function and contributes to vascular stiffness.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Sung Mee
authors.initials: SM
authors.lastname: Jung
authors.forename: Simran
authors.initials: S
authors.lastname: Jandu
authors.forename: Jochen
authors.initials: J
authors.lastname: Steppan
authors.forename: Alexey
authors.initials: A
authors.lastname: Belkin
authors.forename: Steven S
authors.initials: SS
authors.lastname: An
authors.forename: Alina
authors.initials: A
authors.lastname: Pak
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Choi
authors.forename: Daniel
authors.initials: D
authors.lastname: Nyhan
authors.forename: Mark
authors.initials: M
authors.lastname: Butlin
authors.forename: Kayla
authors.initials: K
authors.lastname: Viegas
authors.forename: Alberto
authors.initials: A
authors.lastname: Avolio
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D013314:Stress, Mechanical; D013718:Tensile Strength / Q000502:physiology; D011503:Transglutaminases / Q000096:biosynthesis*; D059289:Vascular Stiffness / Q000502:physiology*
chemical_list: D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: S-nitrosylation; endothelial nitric oxide synthase; nitric oxide; pulse-wave velocity; tensile testing; tissue transglutaminase; vascular stiffness