title: Lysyl oxidase (LOX) in vascular remodelling. Insight from a new animal model.
abstract: Lysyl oxidase (LOX) is an extracellular matrix-modifying enzyme that seems to play a critical role in vascular remodelling. However, the lack of viable LOX-deficient animal models has been an obstacle to deep in LOX biology. In this study we have developed a transgenic mouse model that over-expresses LOX in vascular smooth muscle cells (VSMC) to clarify whether LOX could regulate VSMC phenotype and vascular remodelling. The SM22α proximal promoter drove the expression of a transgene containing the human LOX cDNA. Two stable transgenic lines, phenotypically indistinguishable, were generated by conventional methods (TgLOX). Transgene expression followed the expected SMC-specific pattern. In TgLOX mice, real-time PCR and immunohistochemistry evidenced a strong expression of LOX in the media from aorta and carotid arteries, coincident with a higher proportion of mature collagen. VSMC isolated from TgLOX mice expressed high levels of LOX pro-enzyme, which was properly secreted and processed into mature and bioactive LOX. Interestingly, cell proliferation was significantly reduced in cells from TgLOX mice. Transgenic VSMC also exhibited low levels of Myh10 (marker of SMC phenotypic switching), PCNA (marker of cell proliferation) and MCP-1, and a weak activation of Akt and ERK1/2 in response to mitogenic stimuli. Accordingly, neointimal thickening induced by carotid artery ligation was attenuated in TgLOX mice that also displayed a reduction in PCNA and MCP-1 immunostaining. Our results give evidence that LOX plays a critical role in vascular remodelling. We have developed a new animal model to study the role of LOX in vascular biology.
authors.forename: Mar
authors.initials: M
authors.lastname: Orriols
authors.forename: Anna
authors.initials: A
authors.lastname: Guadall
authors.forename: María
authors.initials: M
authors.lastname: Galán
authors.forename: Ingrid
authors.initials: I
authors.lastname: Martí-Pàmies
authors.forename: Saray
authors.initials: S
authors.lastname: Varona
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.forename: Ana María
authors.initials: AM
authors.lastname: Briones
authors.forename: María A
authors.initials: MA
authors.lastname: Navarro
authors.forename: Alicia
authors.initials: A
authors.lastname: de Diego
authors.forename: Jesús
authors.initials: J
authors.lastname: Osada
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.affiliation: José Martínez-González or Cristina Rodríguez, Centro de Investigación Cardiovascular (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (pabellón Nº 11), Avda. Sant Antoni Maria Claret 167, 08025 Barcelona, Spain, Tel.: +34 93 5565897, Fax: +34 93 5565559, E-mail: crodriguezs@csic-iccc.org; jmartinez@csic-iccc.org.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000378:metabolism; D024501:Nonmuscle Myosin Type IIB / Q000378:metabolism; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D014162:Transfection; D019076:Transgenes; D066253:Vascular Remodeling / Q000235:genetics*; D014945:Wound Healing
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018076:DNA, Complementary; D018809:Proliferating Cell Nuclear Antigen; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D024501:Nonmuscle Myosin Type IIB; C103815:nonmuscle myosin type IIB heavy chain; D018995:Myosin Heavy Chains
keywords: Vascular remodelling; cell proliferation; extracellular matrix; smooth muscle cells