Flow-Dependent Remodeling of Small Arteries in Mice Deficient for Tissue-Type Transglutaminase

Abstract

Abstract-Chronic changes in blood flow induce an adaptation of vascular caliber. Thus, arteries show inward remodeling after a reduction in blood flow. We hypothesized that this remodeling depends on the crosslinking enzyme tissue-type transglutaminase (tTG). Flow-dependent remodeling was studied in wild-type (WT) and tTG-null mice using a surgically imposed change in blood flow in small mesenteric arteries. WT mice showed inward remodeling after 2 days of low blood flow, which was absent in arteries from tTG-null mice. Yet, after continued low blood flow for 7 days, inward remodeling was similar in arteries from WT and tTG-null mice. Studying the alternative pathways of remodeling, we identified a relatively high expression of the plasma transglutaminase factor XIII in arteries of WT and tTG-null mice. In addition, vessels from both WT and tTG-null mice showed the presence of transglutaminase-specific crosslinks. An accumulation of adventitial monocytes/macrophages was found in vessels exposed to low blood flow in tTG-null mice. Because monocytes/macrophages may represent a source of factor XIII, tTG-null mice were treated with liposome-encapsulated clodronate. Elimination of monocytes/macrophages with liposome-encapsulated clodronate reduced both the expression of factor XIII and inward remodeling in tTG-null mice. In conclusion, tTG plays an important role in the inward remodeling of small arteries associated with decreased blood flow. Adventitial monocytes/macrophages are a source of factor XIII in tTG-null mice and contribute to an alternative, delayed mechanism of inward remodeling when tTG is absent.

Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

“…Cumulative data support our concept of a remodeling continuum that allows blood vessels to modify their structural characteristics to accommodate for changes in their neurohumoral and/or mechanical environments (4,29). The incomplete relaxation response we observed upon exposure to the vasodilator cocktail in vivo, or the calcium-free buffer ex vivo, is in accordance with the definition of inward remodeling introduced by Mulvany et al (38) and therefore indicates that inward remodeling processes have been initiated in vessels exposed to 5-HT ϩ L-NAME.…”

The Plastic Nature of the Vascular Wall: A Continuum of Remodeling Events Contributing to Control of Arteriolar Diameter and Structure

“…A third possibility is that there are rapid changes in the extracellular matrix that shrink and stiffen the vascular structure. This possibility is supported by experimental data showing that the activity of the protein cross-linking enzyme, tissue type transglutaminase, is augmented during the remodeling process (4,6,7). Together, these changes would result in a blood vessel with a reduced diameter comprised of vascular smooth muscle cells at or near their control lengths and putatively capable of exhibiting a near full range of contractile activity.…”

Serum protein profiling in mice: Identification of Factor XIIIa as a potential biomarker for muscular dystrophy

“…Factor XIIIa crosslinks fibrin during blood coagulation though its transglutaminase activity, however, there is accumulating evidence that the protein also has roles in cardiovascular biology [26], possibly through macrophage activation [27,28]. Macrophages are known to infiltrate dystrophic muscle [29], which may explain the lower level of this protein in serum.…”