Nuclear Receptor Nur77 inhibits vascular outward remodeling and reduces macrophage accumulation and matrix metalloproteinase levels

AIMS: Structural adaptation of the vessel wall in response to sustained alterations in hemodynamic forces is known as vascular remodeling. Detailed knowledge on the mechanism underlying this vascular response is limited and we aimed to study the function of Nur77 in smooth muscle cells (SMCs) in arterial remodeling. Methods and Results Carotid artery ligation in mice results in flow-induced, outward remodeling of the contralateral carotid artery and we observed enhanced Nur77 expression during this process. Transgenic mice that express Nur77 or its dominant-negative variant denoted as 'DeltaTA' in arterial SMCs, were exposed to carotid artery ligation and after 4 weeks pressure-diameter relationships were measured. Structural outward remodeling is inhibited in Nur77-transgenic mice as compared to wild-type and DeltaTA-transgenic mice. The key determinants of remodeling vascular tone and macrophage accumulation were studied. No difference in contractile and relaxant responses was detected in isolated aorta, carotid and mesenteric artery segments between transgenic and wild-type mice. SMC-specific overexpression of Nur77 in transgenic mice reduced macrophage accumulation and repressed matrix metalloproteinase (MMP)-1 and -9 expression at early time points. MMP2 protein expression was reduced in Nur77 transgenic mice, whereas in DeltaTA-transgenic mice MMP2 expression was increased. CONCLUSION: Nur77 is induced during outward remodeling and inhibits this vascular adaptation in mice. Nur77-mediated inhibition of arterial remodeling involves a reduction in both macrophage accumulation and MMP expression levels