New insights into the role of matrix metalloproteinases in heart angiogenesis induced by exercise

Abstract

Angiogenesis induced by exercise has been observed in both cardiac and skeletal muscle and plays a fundamental role in maintaining tissue function adequate to the increase in metabolic requests. Mechanical and haemodynamic forces are strong starters of angiogenic process via regulation of secondary mediators such as vascular endothelial growth factor (VEGF). A crucial step of vessel sprouting is the degradation of the basement membrane and remodelling of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs). It has long been accepted that MMPs are involved in the angiogenesis, but the exact mechanisms are not well characterized. Cryptic fragments and neo-epitopes released by proteolysis of basement membrane components by MMPs can promote or block capillary growth. MMPs are also involved in the release and activation of growth factors embedded into ECM such as VEGF. In turn, it has been showed in vitro that VEGF can stimulate endothelial and smooth muscle cells to produce MMPs suggesting a reciprocal relationship between VEGF and MMPs. The expression patterns of MMPs are temporally dissociated by those of VEGF in vivo: MMPs and VEGF seem to be independently regulated and involved respectively in sprout formation and capillary proliferation. Little is known about the regulation of MMPs by exercise and the most studies were carried out in the skeletal muscle. The increase in MMP activity is an early and critical feature of angiogenesis in skeletal muscle when initiated by mechanical stimuli which lead to breakage of the basement membrane but not by stimuli such as shear stress that act via the luminal surface of vessels. Although MMPs seem to play a important role in sprouting angiogenesis induced by exercise, in our knowledge their function in exercised hearts has not been still tested. It is known that elevated levels of tissue inhibitors of the MMPs (TIMPs) may contribute to the accumulation of collagen content in the infarcted heart leading to myocardial fibrosis. Therefore, a positive modulation of MMP system by exercise in heart failure-related myocardial remodelling could lead to a ECM with a less fibrous component and more angiogenic sprouting in order to preserve the cardiac function.