Activation of Extracellular Transglutaminase 2 by Mechanical Force in the Arterial Wall

Abstract

Inward remodeling of small arteries occurs after prolonged vasoconstriction, low blood flow, and in several models of hypertension. The cross-linking enzyme, transglutaminases 2 (TG2), is able to induce inward remodeling and stiffening of arteries. The activity of TG2 is dependent on its conformation, which can be open or closed, and on its redox state. Several factors have been shown to be involved in modulating TG2 activity, including Ca²⁺ and GTP/GDP concentrations, as well as the redox state of the environment. This review introduces the hypothesis that mechanical force could be involved in regulating the activity of TG2 during inward remodeling by promoting its open and reduced active state. Several aspects of TG2, such as its structure and localization, are assessed in order to provide arguments that support the hypothesis. We conclude that a direct activation of TG2 by mechanical force exerted by smooth muscle cells may explain the link between smooth muscle activation and inward remodeling, as observed in several physiological and pathological conditions.

Mechanotransduction and extracellular matrix homeostasis

“…In addition, cell-mediated organization of matrix likely mimics the aforementioned residual matrix tension that cells establish in vitro in collagen gels 16, 34 , which would enable the cells to coordinate the organization of both new and pre-existing ECM such that they do not have to actively maintain the tension that they build into to the matrix. Rather, the incorporation of this tension is likely accomplished via the crosslinking of prestressed matrix constituents, a process which may be mechanically regulated as well 53 . In summary, cells often actively organize the matrix through their integrins, with the actomyosin machinery allowing them to pull or push on fibers that can subsequently be entrenched to establish a new mechanical state 53 .…”

“…Rather, the incorporation of this tension is likely accomplished via the crosslinking of prestressed matrix constituents, a process which may be mechanically regulated as well 53 . In summary, cells often actively organize the matrix through their integrins, with the actomyosin machinery allowing them to pull or push on fibers that can subsequently be entrenched to establish a new mechanical state 53 .…”

Role of Mechanotransduction in Vascular Biology

“…Interestingly, cell generated stresses needed to activate TGF-β are ~5 to 9 kPa 78 , similar to typical stresses at focal adhesions 106 , in cells placed within otherwise unloaded matrix 105 , and endogenous levels established in collagen gels by cells 97 . It may be that mechanosensing and the mechanoregulation of cytokines 78 , proteases and their action 74 , or cross-linkers such as transglutaminases 123 that are stored within the ECM are highly complementary, again involving the same intracellular structures and signaling pathways. Finally, transmembrane polycystins appear to contribute to mechanosensing in vascular cells; they often co-localize with stretch-activated calcium channels and modulate their activity 124 .…”

“…In other words, residual matrix tension preserves some cell-mediated changes in matrix organization without requiring continued actomyosin activity, which would be energetically favorable. Transglutaminases may play a role in such entrenchment just as in tissue-level arterial remodeling 30 , noting that matrix bound transglutaminases can be activated by mechanical stress 123 .…”

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

“…Direct activation of TG2 by cellular traction forces has been demonstrated for vascular smooth muscle cells [85]. The extracellular domain of the transmembrane proteoglycan syndecan-4 has been shown to promote collagen cross-linking through regulation of cell surface TG2 trafficking and activity [86,87,88], and collagen cross-linking by LOX in in vitro [89], suggesting that cells may regulate ECM structure and thus TGFβ bioavailability through inside-out signaling.…”