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.

Signaling by S-nitrosylation in the heart

“…Additionally, SNO of β-arrestin 2 has been shown to promote its localization with the clathrin heavy chain/β-adaptin complex, thus leading to internalization into endosomal vesicles [28]. Transglutaminase crosslinks extracellular matrix proteins promoting aortic stiffness; SNO of transglutaminase restricts its localization to the cytosol and reduces the crosslinking of matrix proteins [29]. SNO of apurinic-apyrimidinic endonuclease 1, a major DNA repair enzyme, triggers the export of the enzyme from the nucleus to the cytosol [30].…”

Proinflammation of Aging Central Arteries: A Mini-Review

“…The activity of tissue transglutaminase (TG2), which catalyzes the crosslinking of proteins, increases in the old arterial wall [65] and is closely regulated by NO bioavailability [66, 67]. Activated TG2 up-regulates calcification promoter genes, i.e.…”

Measuring Ascending Aortic Stiffness <em>In Vivo</em> in Mice Using Ultrasound

“…To determine compliance, the vessel segment is mounted on a pressure myograph 13,14 . Pressure within the vessel is increased step-wise and the resulting change in diameter is tracked using video microscopy.…”

“…In vivo, in addition to wall content, vascular stiffness is influenced dynamically by smooth muscle tone and blood pressure 13,15,16 . PWV is the most widely used method for measuring in vivo aortic stiffness in experimental models.…”

“…Measurement methods that incorporate the influence of blood pressure with the passive properties of the vascular wall and the effects of vasoactive mediators that alter tone would yield a physiologically relevant index of arterial stiffness. This approach is implemented by measuring PWV invasively using a catheter with two pressure sensors separated at a fixed distance 13 . This dual pressure catheter is inserted into the aorta and vasoactive drugs, such as phenylephrine or sodium nitroprusside, are infused intravenously through a venous catheter to raise and lower arterial pressure.…”