Transglutaminases in Vascular Biology: Relevance for Vascular Remodeling and Atherosclerosis

Abstract

The transglutaminase (Tgase) family consists of nine known members of whom at least three are expressed in the vascular system: type 1 Tgase, type 2 Tgase and factor XIII. The cross-linking of proteins is a characteristic feature of Tgases, of well-known importance for stabilizing the blood clot and providing mechanical strength to tissues. However, recent data suggest that Tgases play a role in several other processes in vascular biology. These newly discovered areas include endothelial barrier function, small artery remodeling, and atherosclerosis.

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.…”

“…The cross-linked collagen thus mechanically constrains the vascular wall. However, it has also been recognized that other activities of tissue-type transglutaminase may participate in vascular remodeling (7). These activities include the capacity of the enzyme to act as a G protein coupled to different agonist receptors, its capacity to participate in the formation of intracellular stress fibers, and its capacity to activate the Rho kinase signaling pathway.…”

Regulation of Platelet-derived Growth Factor Receptor Function by Integrin-associated Cell Surface Transglutaminase

“…Accordingly, the reported contribution of tTG to dermal wound healing and angiogenesis (31) could be explained at least in part by the activation of PDGFR signaling via cell surface tTG. Furthermore, a significant increase in tTG expression during liver and renal fibrosis (32), atherosclerosis (18,33), and in metastatic cancer cells of diverse tissue origin (19) all suggest an essential role of this protein in the in vivo processes that involve hyperactivation of PDGFR signaling and promote cell survival, proliferation, and migration leading to inflammation and tissue fibrosis (5). Finally, the ability of autoantibodies to PDGFR, found in patients with systemic sclerosis (34) and chronic graft-versushost disease (35), to stimulate receptor activation, downstream signaling, and promote fibrosis due to enhancement of collagen synthesis may be mimicked by autoantibodies to tTG present in celiac disease and rheumatoid arthritis (36).…”

“…These studies reveal a novel function of tTG in coupling the adhesion-mediated and growth factor-dependent signaling pathways. They suggest that this tTG activity might be involved in pro-inflammatory function of this protein in normal wound healing and tissue fibrosis (18), vascular remodeling (19), and tumor metastasis (20).…”

Getting Neointimal

“…Furthermore, it will be interesting to know how heparanase interacts with the other ECM enzymes important for vascular structure, eg, the metalloproteinases 18 and transglutaminases. 19 Nearly a decade ago, such an interaction between metalloproteinases and heparanase was suggested to be important for smooth muscle cell phenotype. 20 An understanding of the interplay between the cellular and extracellular factors in the vessel wall is critically important to our comprehension of how arterial structure is regulated and how it can be compromised.…”