Abstract 45: Reduced Vascular Remodeling and Improved Endothelial Function in Transglutaminase 2 Knock-Out Mice Treated with Angiotensin II

Abstract

Transglutaminase 2 (TG2) may modulate cell-matrix interactions by inducing cross-linking of proteins. We previously demonstrated that angiotensin II (Ang II) positively regulated TG2 expression in vascular smooth muscle cells from SHR. Here we hypothesized that Ang II induces vascular remodeling in part through TG2. TG2-knockout mice (TG2-K/O, 8 weeks old, 6 for each group) and age-matched wild type (WT) control mice were treated or not with Ang II (400 ng/kg/min) for 14 days. Blood pressure (BP) was measured by tail-cuff method. Endothelium-dependent and -independent relaxation were assessed by concentration-response curves to acetylcholine (1 nM to 100 μM) ± L-NAME (100 μM) and sodium nitroprusside (10 nM to 1 mM) respectively, in mesenteric arteries pre-contracted with norepinephrine (10 μM). Media-to-lumen ratio (M/L) and cross sectional area (CSA) were evaluated on pressurized preparations. BP was higher in TG2-K/O mice compared to WT (120.3±1.3 mmHg vs 88.3±1.9 mmHg, P<0.05), Ang II infusion significantly increased BP only in WT (+28% vs untreated WT, P<0.05), whereas BP was unchanged in TG2-K/O after Ang II infusion. Endothelium-dependent relaxation was similarly preserved in untreated WT, TG2-K/O and Ang II-treated TG2-K/O. Ang II infusion impaired acetylcholine-induced relaxation only in WT (-50% vs untreated WT, P<0.05). L-NAME blunted acetylcholine-induced relaxation in all the groups except in Ang II-treated WT, suggesting an impairment of NO production only in this group. Endothelium-independent relaxation was similar in all groups. TG2-K/O presented reduced M/L as compared to WT (4.8±0.3% vs 6.5±0.2%, P<0.05). Ang II infusion increased M/L only in WT (+13% vs untreated WT, P<0.05). M/L resulted unchanged in TG2-K/O after Ang II infusion. CSA was similar in all groups. In conclusion, despite the higher BP values, TG2-K/O presented improved vascular remodeling compared to WT. Ang II failed to increase M/L and impair endothelial function in TG2-K/O. Hence TG2 may play a role in Ang II-induced vascular structural and functional alterations.