The Identification of In Vivo Angiogenesis and Fibrosis in Myocardial Infarction Using Positron Emission Tomography.

Integrins are a group of molecules responsible for intercellular adhesion and signalling. They comprise a superfamily of heterodimeric receptors that are composed of 18 different α and β subunits. In combination, they can generate 24 different receptor subtypes with a range of physiological and pathophysiological functions [Takada et al, 2007]. The αvβ3 receptor is an integrin that is found at low levels on mature endothelial cells but is markedly up regulated on endothelial cells of actively growing blood vessels. It was previously known as the vitronectin receptor although it was subsequently found to bind many other ligands including fibrinogen, fibronectin, laminin, thrombospondin, von Willebrand factor, and certain collagen subtypes. These features are also seen with the αvβ5 integrin receptor, with both receptors recognising the arginine-glycine-aspartate (RGD) motif present on these ligands.

1.1.2 Role of αvβ3 and αvβ5 Integrins in Cardiovascular Disease

The expression of αvβ3 and αvβ5 receptors is up regulated in a number of diseased states and this has been particularly well characterised in the angiogenesis associated with tumour growth and metastases [Friedlander et al, 1995; Brooks et al, 1994]. However, there are many potential roles for this integrin pathway in cardiovascular disease including myocardial infarction, atherosclerosis, restenosis, aortic stenosis and aneurysm disease that have been relatively unexplored.

1.1.2.1 Myocardial Infarction

After myocardial infarction, there is an intense inflammatory response followed by angiogenesis and fibrosis. During this time of healing and reparation, there is marked up regulation of integrins in order to orchestrate efficient myocardial healing. For the αvβ3 and αvβ5 integrin receptors, this reflects both angiogenesis and fibrosis given their ligand binding properties [van den Borne et al, 2008; Higuchi et al, 2008]. This is at the centre of early and delayed left ventricular remodelling in the infarct and peri-infarct zone. The early phase is dominated by angiogenesis to restore vascular integrity and tissue perfusion with αvβ3 and αvβ5 receptors being up regulated and expressed on activated endothelial cells within newly forming vessels [Higuchi et al, 2008]. With subsequent myocardial healing and remodelling, activation of fibroblasts and differentiation into myofibroblasts requires αvβ3 and αvβ5 receptor interactions and is central to the development of fibrosis [van den Borne et al, 2008]. Maladaptive fibrotic responses and adverse left ventricular remodelling may underlie the development of heart failure following myocardial infarction. These processes and pathways may also play a role in the development of myocardial fibrosis in other conditions such as left ventricular hypertrophy associated with aortic stenosis [Dweck et al, 2011].