TR3 Nuclear Orphan Receptor Prevents Cyclic Stretch-Induced Proliferation of Venous Smooth Muscle Cells

Abstract

In coronary artery bypass surgery , the patency of arterial grafts is higher than that of venous grafts because of vein-graft disease , which involves excessive proliferation of venous smooth muscle cells (SMCs) and subsequent accelerated atherosclerosis. We studied the function of TR3 nuclear orphan receptor (TR3) in the early response of SMCs to mechanical strain , a major initiator of vein-graft disease. We demonstrate that TR3 expression is induced in human saphenous vein segments exposed ex vivo to whole-blood perfusion under arterial pressure. Cultured venous SMCs challenged by cyclic stretch displayed TR3 induction and enhanced DNA synthesis , whereas SMCs derived from the internal mammary artery remained quiescent. Small-interfering RNA-mediated knockdown of TR3 and adenovirus-mediated overexpression of TR3 in venous SMCs enhanced and abolished stretch-induced DNA synthesis , respectively. Accordingly, in organ cultures of wild-type murine vessel segments exposed to cyclic stretch, p27Kip1 was down-regulated, whereas expression of this cell cycle inhibitor was unaffected by cyclic stretch in TR3-transgenic vessels, concordant with a lower proliferative response. Finally, stretch-mediated proliferation was inhibited by 6-mercaptopurine, an agonist of TR3. In conclusion, TR3 represents inhibitory mechanisms to restrict venous SMC proliferation and may contribute to prevention of veingraft disease.

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

“…Involvement of the transcription factor NR4A1 The induction of NR4A1 has been shown to play a crucial role in the inhibition of proliferation of vascular smooth muscle cells [20][21][22][23][24]. Therefore, we analyzed effects of nucleotides on the expression of the early gene NR4A1.…”

“…Previous studies indicate a cellular expression of transcription factors of the NR4A subfamily in human atherosclerotic lesions and an involvement of these transcription factors in regulatory mechanisms during atherosclerosis [21]. Genetically induced overexpression of NR4A1 and drug-induced induction of NR4A1 are known to inhibit proliferation of both arterial and venous smooth muscle cells [21][22][23][24]. In contrast to the effects mediated by adenosine A 2B receptors, activation of adenosine A 3 receptors by the selective agonist 2-chloro-IB-MECA increased the proliferation of cultured human coronary smooth muscle cells [25].…”

Biomechanical regulation of vascular smooth muscle cell functions: from in vitro to in vivo understanding

“…Aortic VSMCs do not show a significant increase in growth when compared with unstretched controls after stretching at 0.05 and 1 Hz. By contrast, stretchings of venous VSMCs both at 0.05 and 1 Hz result in a significant increase in growth when compared with static controls [90,91]. Mechanical stretch increases the synthetic-phenotype behaviour of injured VSMCs in the arterial intima in response to in vitro balloon angioplasty injury [16,81].…”

The Orphan Nuclear Receptor Nur77 Suppresses Endothelial Cell Activation Through Induction of IκBα Expression

“…8,9 Overexpression of Nur77 has been shown to inhibit cell proliferation and attenuate vascular injury-induced neointimal formation in vivo. 10,11 NR4A nuclear receptors are also induced in ECs by several stimuli, such as hypoxia, TNF-␣, and vascular endothelial growth factor, and modulate EC growth, survival, and angiogenesis. [12][13][14] At present, whether or not NR4A nuclear receptors modulate inflammatory responses in ECs, however, is unknown.…”