Abstract-Remodeling of small arteries is essential in the long-term regulation of blood pressure and blood flow to specific organs or tissues. A large part of the change in vessel diameter may occur through non-growth-related reorganization of vessel wall components. The hypothesis was tested that tissue-type transglutaminase (tTG), a cross-linking enzyme, contributes to the inward remodeling of small arteries. The in vivo inward remodeling of rat mesenteric arteries, induced by low blood flow, was attenuated by inhibition of tTG. Rat skeletal muscle arteries expressed tTG, as identified by Western blot and immunostaining. In vitro, activation of these arteries with endothelin-1 resulted in inward remodeling, which was blocked by tTG inhibitors. Small arteries obtained from rats and pigs both showed inward remodeling after exposure to exogenous transglutaminase, which was inhibited by addition of a nitric oxide donor. Enhanced expression of tTG, induced by retinoic acid, increased inward remodeling of porcine coronary arteries kept in organ culture for 3 days. The activity of tTG was dependent on pressure. Inhibition of tTG reversed remodeling, causing a substantial increase in vessel diameter. In a collagen gel contraction assay, tTG determined the compaction of collagen by smooth muscle cells. Collectively, these data show that small artery remodeling associated with chronic vasoconstriction depends on tissue-type transglutaminase. This mechanism may reveal a novel therapeutic target for pathologies associated with inward remodeling of the resistance arteries. hronic alteration in the hemodynamic profile is associated with arterial remodeling. Both large and small arteries adapt to a reduction in blood flow with a decrease in lumen diameter, 1,2 and in several forms of hypertension, the wall-to-lumen ratio of arteries is increased. 3,4 Although hypertrophy of the vessel wall may contribute to this remodeling in larger arteries, in resistance arteries, it mainly involves a geometrical reorganization of wall components around a smaller lumen. 5 Thus, in essential hypertension, the reduction in lumen size of resistance arteries appears to be eutrophic, ie, without a change in the amount of wall material. 3 In the process of inward remodeling, the reorganization of smooth muscle cells, induced by chronic vasoconstriction, may be an early event. 6 Whereas inward remodeling is identified as an important risk factor for cardiovascular events, 7 the mechanisms that control blood vessel caliber under physiological and pathological conditions are incompletely understood.Tissue-type transglutaminase (tTG), also called transglutaminase type 2, belongs to a family of enzymes that includes coagulation factor XIII. tTG is ubiquitously expressed and present both within the cells and at the cell surface, where it associates with integrins. 8 The enzyme catalyzes the formation of an N⑀ (␥-glutamyl)lysine cross-link, a bond between a glutamine residue and the primary amino group of either a peptide-bound lysine or a polyamine. M...

. Atherogenic region and diet diminish glycocalyx dimension and increase intima-to-media ratios at murine carotid artery bifurcation. Am J Physiol Heart Circ Physiol 290: H915-H920, 2006. First published September 9, 2005 doi:10.1152/ajpheart.00051.2005.-It was hypothesized that endothelial glycocalyx perturbation contributes to increased vulnerability of the arterial wall exposed to atherogenic risk factors. Glycocalyx and intima-to-media ratios (IMR) were studied at a low-and a high-risk region within the murine carotid artery (common region) and internal carotid branch (sinus region) in control C57BL/6J (C57BL6) and age-matched C57BL/6J/apoE*3-Leiden (apoE*3; on an atherogenic diet) mice. Electron micrographs revealed significantly thinner glycocalyces flow; permeability THE IMPORTANCE of an endothelial cell surface glycocalyx has been established by functional studies and electron microscopic observations. The endothelial glycocalyx shields the vascular wall from flowing blood, limits leakage of fluid and macromolecules across its endothelial lining, forms a mechanical barrier against adhesion of leukocytes and platelets to the endothelial surface, and stimulates endothelial NO release by mechanotransducing fluid shear stresses (3-5, 15, 21, 23). Although reduced levels of surface-bound sialic acids (9) and increased endothelial permeability and susceptibility to atherosclerotic lesion formation (10) have been found to coincide with arterial branch points and curvatures, little is known about the contribution of glycocalyx perturbation to the increased vascular vulnerability of high-atherogenic risk areas.Atherosclerotic lesions within the arterial tree develop at predictable vessel geometries, e.g., arterial branching and curvatures, and constraints on vessel motion by the surrounding tissues, which lead to local flow instabilities and separations (24). Such lesions can be detected and visualized as changes in vascular wall properties and quantified as intima-to-media ratios

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.