Saturday, 7th December 2019

Extracellular matrix remodeling in the cardiovascular system

2016 04 07 Grupo F Rodriguez Pascual400px


Fernando Rodríguez Pascual





Research summary:

Over the years, our understanding of the functions of the extracellular matrix has evolved from the traditional concept of a static "glue" holding cells into tissues to the more sophisticated one of a dynamic biomaterial that provides strenght and elasticity, as well as points of interactions with cell surface receptors, and availability of growth factors. Today it has become clear that proper formation and assembly of extracellular matrix components is essential for cell and tissue homeostasis, and that defects in these processes are associated with several human disorders.

  Fig 01 EngB300px

Lysyl oxidase (LOX) inhibition induces ascending aortic dilatation in Marfan mice. (A) Ascending aortic diameter as measured by echocardiography prior to the beginning of the treatment (baseline), and 4 and 8 weeks after the administration of the LOX inhibitor, b-aminopropionitrile (BAPN), or placebo in Marfan mice. Values are means + SEM. *P<0.05. (B) Gross morphology of representative aortas of mice treated with placebo or BAPN during 8 weeks





Matrix-related diseases arise from both defects in the properties of extracellular matrix components, as occurred in certain heritable disorders, such as Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, and many other connective tissue diseases, as well as in conditions characterized with an excess of production and deposition of extracellular matrix components, generally termed as fibrosis, a pathophysiological circumstance that is common to a number of chronic diseases, including idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis and nephrosclerosis, among others.

In vertebrates, where the circulatory system consists of a central pump (the heart) and a network of tubes (the vasculature) through which the blood is continuously circulated, the extracellular matrix plays an essential role in determining the mechanical properties of the vascular and cardiac tissues. Main extracellular matrix components in the cardiovascular system, namely elastin and collagen, are synthesized and secreted to the extracellular medium as soluble forms (tropocollagen and tropoelastin) that are heavily processed to form supramolecular complexes constituting the basis of a tremendous diversity of matrix-containing suprastructures. Lysyl oxidase family of enzymes catalyze the formation of cross-linkages in collagen and elastin fibers and therefore are essential factors in the process of stabilization and maturation of the extracellular matrix. Our group investigates the molecular mechanisms that control the expression and activity of lysyl oxidase enzymes, as well as the pathophysiological relevance of these factors in the context of cardiovascular diseases, with particular focus on their role in the vascular complications associated to Marfan syndrome and in the cardiac fibrosis associated to the myocardial infarction. By using in vitro and in vivo approaches, our laboratory analyzes the contribution of these matrix remodeling enzymes to extracellular matrix homeostasis both in health and disease, as well as their validation for potential medical application.


Relevant publications:

1. Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction.

González-Santamaría J, Villalba M, Busnadiego O, López-Olañeta MM, Sandoval P, Snabel J, López-Cabrera M, Erler JT, Hanemaaijer R, Lara-Pezzi E, Rodríguez-Pascual F. Cardiovasc Res. 2016 Jan 1;109(1):67-78. doi: 10.1093/cvr/cvv214. Epub 2015 Aug 10. PubMed PMID: 26260798.

2. Origin and evolution of lysyl oxidases.
Grau-Bové X, Ruiz-Trillo I, Rodriguez-Pascual F. Sci Rep. 2015 May 29;5:10568. doi: 10.1038/srep10568. PubMed PMID: 26024311; PubMed Central PMCID: PMC4448552.

3. Elevated expression levels of lysyl oxidases protect against aortic aneurysm progression in Marfan syndrome.
Busnadiego O, Gorbenko Del Blanco D, González-Santamaría J, Habashi JP, Calderon JF, Sandoval P, Bedja D, Guinea-Viniegra J, Lopez-Cabrera M, Rosell-Garcia T, Snabel JM, Hanemaaijer R, Forteza A, Dietz HC, Egea G, Rodriguez-Pascual F. J Mol Cell Cardiol. 2015 Aug;85:48-57. doi: 10.1016/j.yjmcc.2015.05.008. Epub 2015 May 16. PubMed PMID: 25988230.

4. Vascular smooth muscle cell phenotypic changes in patients with Marfan syndrome.
Crosas-Molist E, Meirelles T, López-Luque J, Serra-Peinado C, Selva J, Caja L, Gorbenko Del Blanco D, Uriarte JJ, Bertran E, Mendizábal Y, Hernández V, García-Calero C, Busnadiego O, Condom E, Toral D, Castellà M, Forteza A, Navajas D, Sarri E, Rodríguez-Pascual F, Dietz HC, Fabregat I, Egea G. Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):960-72. doi: 10.1161/ATVBAHA.114.304412. Epub 2015 Jan 15. PubMed PMID: 25593132.

5. LOXL4 is induced by transforming growth factor β1 through Smad and JunB/Fra2 and contributes to vascular matrix remodeling.
Busnadiego O, González-Santamaría J, Lagares D, Guinea-Viniegra J, Pichol-Thievend C, Muller L, Rodríguez-Pascual F. Mol Cell Biol. 2013 Jun;33(12):2388-401. doi: 10.1128/MCB.00036-13. Epub 2013 Apr 9. PubMed PMID: 23572561; PubMed Central PMCID: PMC3700097.


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