Sex-mediated effects of transglutaminase 2 inhibition on endothelial function in human resistance arteries from diabetic and non-diabetic patients

Transglutaminase 2 (TG2) is an enzyme with multiple conformations. In its open conformation, TG2 exhibits transamidase activity linked to fibrosis, arterial remodeling, and endothelial dysfunction, a process enhanced by high glucose in endothelial cells. However, the closed conformation of TG2 contributes to transmembrane signaling and nitric oxide (NO)-dependent vasorelaxation. LDN 27219, a reversible allosteric inhibitor, stabilizes TG2 in its closed conformation. &#160;We examined whether pharmacological modulation of TG2 into its closed conformation induces vasorelaxation and enhances endothelium-dependent and independent relaxation in resistance arteries from age-matched diabetic (n=14) and non-diabetic patients (n=14) (age 71  (SEM: ±2).</p> &#160;Subcutaneous arteries (diameter 133–1013 µm) were isolated from abdominal fat biopsies. TG2 mRNA expression and transamidase activity were assessed via RT-qPCR and 5-biotin(amido)pentylamine (5-BP) incorporation, while vascular reactivity was measured using wire myography. TG2 mRNA was highly expressed without significant differences between the groups and LDN 27219 induced concentration-dependent vasorelaxation in arteries from both groups. Sex-specific analysis revealed that potentiation of  acetylcholine-induced vasorelaxation by LDN 27219 was driven by increased TG2 expression in non-diabetic females, while no effect was observed in arteries from non-diabetic males. Among diabetic patients, LDN 27219 increased maximal acetylcholine-induced vasorelaxation in males only. LDN 27219 did not affect endothelium-independent relaxation to sodium nitroprusside in either group.</p> In conclusion, TG2 is expressed in human resistance arteries, and LDN 27219 induced vasorelaxation, selectively enhancing ACh relaxation in non-diabetic females, likely due to increased TG2 expression. This finding underscores the importance of sex differences in TG2 modulation of vasorelaxation.