Abstract 298: Roles Of Tet2 In Vascular Regeneration For Peripheral Artery Disease

Abstract

Peripheral artery disease (PAD) is the manifestation of atherosclerosis in the extremity, causing blockage of blood vessels that reduces blood flow to the lower limb (ischemia). End-stage PAD patients require limb amputation, with increased risk of morbidity and mortality from heart attacks. Although PAD affects >200 million individuals worldwide, surgery remains the only endpoint option that itself is associated with significant morbidity and mortality. Novel treatment for PAD is therefore urgently needed. Despite vascular smooth muscle cells (VSMC) being essential for normal vascular formation and repair, their role in PAD pathogenesis has been largely ignored. Our lab has long been specialised in studying VSMC biology, and was the first to identify a DNA demethylase, Tet2, as a master regulator of VSMC functions ( Liu et al, Circulation. 2013 ). We found without Tet2, VSMCs form pathological and weakened arteries that lead to restenosis, the precursor of atherosclerosis. Given the vital role VSMC in vessel formation, we hypothesise that restoring Tet2 expression to ischaemic tissues is critical for promoting angiogenesis, blood flow recovery and to prevent tissue caused by PAD. Using a VSMC-specific Tet2 knockout (VSM- Tet2 KO ) mouse line generated by the Liu lab at VCCRI, we studied the vasculo-protective role of TET2 in PAD by mimicking PAD through femoral artery ligation. Our preliminary data demonstrates: (1) severe tissue necrosis and amputation in the knockout mice following surgery that is not observed in controls (2) Loss of Tet2 reduces blood flow to the foot as suggested by laser doppler measurements. (3) Significantly retarded neovascularisation in ischemic muscle regions displayed by micro-computer tomography scans . These are the first data to demonstrate Tet2’s role in PAD.