title: Over-expression of neuron-derived orphan receptor-1 (NOR-1) exacerbates neointimal hyperplasia after vascular injury.
abstract: We have previously shown that NOR-1 (NR4A3) modulates the proliferation and survival of vascular cells in culture. However, in genetically modified animal models, somewhat conflicting results have been reported concerning the involvement of NOR-1 in neointimal formation after vascular injury. The aim of this study was to generate a transgenic mouse model over-expressing NOR-1 in smooth muscle cells (SMCs) and assess the consequence of a gain of function of this receptor on intimal hyperplasia after vascular injury. The transgene construct (SM22-NOR1) was prepared by ligating the full-length human NOR-1 cDNA (hNOR-1) and a mouse SM22α minimal promoter able to drive NOR-1 expression to SMC. Two founders were generated and two stable transgenic mouse lines (TgNOR-1) were established by backcrossing the transgene-carrying founders with C57BL/6J mice. Real-time PCR and immunohistochemistry confirmed that hNOR-1 was mainly targeted to vascular beds such as aorta and carotid arteries, and was similar in both transgenic lines. Vascular SMC from transgenic animals exhibit increased NOR-1 transcriptional activity (assessed by electrophoretic mobility shift assay and luciferase assays), increased mitogenic activity (determined by [(3)H]-thymidine incorporation; 1.58-fold induction, P < 0.001) and increased expression of embryonic smooth muscle myosin heavy chain (SMemb) than wild-type cells from control littermates. Using the carotid artery ligation model, we show that neointima formation was increased in transgenic versus wild-type mice (2.36-fold induction, P < 0.01). Our in vivo data support a role for NOR-1 in VSMC proliferation and vascular remodelling. This NOR-1 transgenic mouse could be a useful model to study fibroproliferative vascular diseases.
authors: Centro de Investigación Cardiovascular, CSIC-ICCC, IIB-Sant Pau, Barcelona, Spain.
authors: Ricardo
authors: R
authors: Rodríguez-Calvo
authors: Anna
authors: A
authors: Guadall
authors: Olivier
authors: O
authors: Calvayrac
authors: María A
authors: MA
authors: Navarro
authors: Judith
authors: J
authors: Alonso
authors: Beatriz
authors: B
authors: Ferrán
authors: Alicia
authors: A
authors: de Diego
authors: Pedro
authors: P
authors: Muniesa
authors: Jesús
authors: J
authors: Osada
authors: Cristina
authors: C
authors: Rodríguez
authors: José
authors: J
authors: Martínez-González
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; C091333:Nr4a3 protein, rat; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone