Small Artery Remodeling Depends on Tissue-Type Transglutaminase

Abstract

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...

Roles of transglutaminases in cardiac and vascular diseases

“…Inhibitors of TG2 block inward remodeling that was induced by endothelin-1. Enhanced expression of endogenous TG2 or the application of exogenous TG2 increases inward remodeling in several animal models (94). In a porcine model of renal artery stenosis, simvastatin inhibited the inward remodeling of the intrarenal microvasculature, partly by decreasing the upregulation of TG2 expression in the ischemic kidney (95).…”

“…Interestingly, the activity of TG2 appears to be regulated, in part, by the application of pressure to the arterial wall (94). Both TG2 and FXIII transglutaminase activities are also regulated by nitric oxide.…”

Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries

“…20,22,23,32,33,37 In addition to being a model that mimics the remodeling that occurs in hypoperfused tissues, LF remodeling has been shown to be equivalent to the eutrophic inward remodeling observed in several types of hypertension, such as endothelin-1-dependent hypertension and L-NAME-induced hypertension. 10 The main finding of this study is that the diameter reduction because of a decrease in blood flow in RAs was prevented by perindopril and candesartan, but not by hydralazine, suggesting selective involvement of angiotensin II and of its AT1R. The AT2R was not involved in this remodeling (see Supplementary information).…”

“…This contraction is then stabilized by the activation of tissuetransglutaminases. 10 Using mice lacking tissue angiotensin I-converting enzyme, Hilgers et al 11 showed that this enzyme has a major role in hyperplasic inward remodeling of the carotid artery after blood flow cessation. In mesenteric RAs, we have previously shown that acute stimulation of the endothelium by flow (shear stress) induces vasodilation, which is modulated by the local production of angiotensin II.…”

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

“…Understanding the mechanisms which may modulate resistance arterial eutrophic remodelling is thus important, but these remain poorly understood. Prolonged vasoconstriction appears important, which, in itself may modulate re-organisation via the activities of cross-linking enzymes such as tissue-type transglutaminase and/ or integrins (Bakker et al, 2002(Bakker et al, , 2005Heerkens et al, 2006). It has been proposed that initial eutrophic remodelling may be an energetically favourable adaptive mechanism to normalise wall stress to maintain adequate blood flow, whilst a growth response, which may be observed in advanced or secondary hypertension, is related to a greater adverse prognosis (Izzard et al, 2006;Heagerty et al, 2010).…”