Objective: Increased vascular stiffness is a growing epidemic in the western world due to the increased incidence of hypertension, obesity, and shift of population demographics to the elderly. Vascular stiffening is highly predictive of major adverse cardiovascular events. Therefore, there is significant interest in identifying and characterizing target proteins to prevent or even reverse vascular stiffening. The structural elements of the vascular wall, namely the extracellular matrix and the smooth muscle cells (SMCs), contribute to the overall stiffness of the vessel. Tissue transglutaminase (TG2) is a multifunctional protein that is highly expressed in the vasculature. While the contribution of TG2’s crosslinking function to vascular remodeling and stiffening have been previously described, the role of its other functions in vascular function and stiffness remain poorly understood. In this study, we aimed to determine the crosslinking-dependent and –independent roles of tissue transglutaminase in vascular stiffness and function. Results: SMCs from TG2-/- mice had delayed adhesion, accelerated deadhesion, reduced motility in response to serum, and accelerated proliferation rates when compared with those from WT. SMCs lacking TG2 expression were stiffer with higher storage and loss moduli over 5-decades of frequency and had decreased cytoskeletal remodeling events than those expressing TG2. Collagen assembly was delayed in TG2-/- SMCs when compared with WT SMCs and recovered with adenoviral transduction of TG2. Intact and decellularized aortic rings from WT mice were stiffer than those from TG2-/- mice. Incubation of aortic rings from TG2-/- mice with guinea pig liver TG2 protein resulted in an increase in stiffness independent of crosslinking function. TG2 regulated contractility of SMCs as evidenced by a significant decrease in IC50 in response to phenylephrine in TG2-/- mice. Role of TG2 in human disease was examined by using a 99-feature tissue microarray composed of human coronary artery segments. TG2 protein and TG-crosslink abundance were similar in all samples. Fibronectin protein expression and colocalization of TG2 and fibronectin were significantly higher in plaques when compared with vascular media. Conclusions: TG2 can acutely alter vascular stiffness by altering SMC contractility independent of its crosslinking function. In the long term, TG2 can contribute to vascular stiffness by altering SMC proliferation and matrix remodeling.

Tissue transglutaminase plays a multifunctional role in vascular mechanics

252nd National Meeting (2016)

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