Thymidine Phosphorylase Promotes Abdominal Aortic Aneurysm via VSMC Modulation and Matrix Remodeling in Mice and Humans

Abstract

Background: Thymidine phosphorylase (TYMP) promotes platelet activation and thrombosis while suppressing vascular smooth muscle cell (VSMC) proliferation. Both processes are central to the development and progression of abdominal aortic aneurysms (AAAs). We hypothesize that TYMP plays a role in AAA development.

Methods: Male wild-type (WT) C57BL/6J and Tymp^−/− mice, fed a Western diet (WD) (TD.88137), were subjected to the 4-week Ang II infusion–induced AAA model. AAA progression was monitored by echography and confirmed through necropsy. Whole-body inflammation was assessed using a plasma cytokine array. Mechanistic studies were conducted using TYMP-overexpressing rat VSMC cell lines and primary VSMCs cultured from WT and Tymp^−/− mouse thoracic aortas. Histological studies were performed on human AAA and normal aorta samples.

Results: Elevated TYMP levels were observed in human AAA vessel walls. While WT mice exhibited a 28.6% prevalence of Ang II infusion–induced AAA formation, Tymp^−/− mice were protected. TYMP enhanced MMP2 expression, secretion, and activation in VSMCs, which was inhibited by tipiracil, a selective TYMP inhibitor. Systemically, TYMP promoted proinflammatory cytokine expression, and its absence attenuated TNF-α-induced MMP2 and AKT activation. WT VSMCs treated with platelets lacking TYMP showed a higher proliferation rate than cells treated with WT platelets. Additionally, TYMP increased activated TGFβ1 expression in cultured VSMCs and human AAA vessel walls. In WT VSMCs, TYMP augmented thrombospondin-1 type 1 repeat domain (TSR)–stimulated TGFβ1 signaling, increasing connective tissue growth factor and MMP2 production. TSR also enhanced AKT activation in WT VSMCs but had the opposite effect in Tymp^−/− cells. TSR-enhanced MMP2 activation in WT VSMCs was attenuated by LY294002 (a PI3K inhibitor) but not by SB431542 (a TGFβ1 inhibitor); both inhibitors had indiscernible effects on Tymp^−/− VSMC.

Conclusion: TYMP emerges as a novel regulatory force in vascular biology, influencing VSMC function and inflammatory responses to promote AAA development.