Abstract
Intraplaque angiogenesis increases the chance of unstable atherosclerotic plaque rupture and thrombus formation leading to myocardial infarction. Basic Fibroblast Growth Factor (bFGF) plays a key role in angiogenesis and inflammation and is involved in the pathogenesis of atherosclerosis. Therefore, we aim to test K5, a small molecule bFGF-inhibitor, on remodelling of accelerated atherosclerotic vein grafts lesions in ApoE3*Leiden mice. K5-mediated bFGF-signalling blockade strongly decreased intraplaque angiogenesis and intraplaque hemorrhage. Moreover, it reduced macrophage infiltration in the lesions by modulating CCL2 and VCAM1 expression. Therefore, K5 increases plaque stability. To study the isolated effect of K5 on angiogenesis and SMCs-mediated intimal hyperplasia formation, we used an in vivo Matrigel-plug mouse model that reveals the effects on in vivo angiogenesis and femoral artery cuff model to exclusively looks at SMCs. K5 drastically reduced in vivo angiogenesis in the matrigel plug model while no effect on SMCs migration nor proliferation could be seen in the femoral artery cuff model. Moreover, in vitro K5 impaired endothelial cells functions, decreasing migration, proliferation and tube formation. Our data show that K5-mediated bFGF signalling blockade in hypercholesterolemic ApoE3*Leiden mice reduces intraplaque angiogenesis, haemorrhage and inflammation. Therefore, K5 is a promising candidate to stabilize advanced atherosclerotic plaques.
Highlights
Intraplaque angiogenesis increases the chance of unstable atherosclerotic plaque rupture and thrombus formation leading to myocardial infarction
In the present study we found that K5 mediated inhibition of Basic Fibroblast Growth Factor (bFGF) reduces intraplaque angiogenesis and intraplaque haemorrhage in a model for accelerated atherosclerosis using vein graft surgery in ApoE3*Leiden mice
We demonstrate that K5 is able to impair endothelial cells (ECs) migration, proliferation and tube formation due to a reduced FGFR1 activation in vitro
Summary
Intraplaque angiogenesis increases the chance of unstable atherosclerotic plaque rupture and thrombus formation leading to myocardial infarction. K5-mediated bFGF-signalling blockade strongly decreased intraplaque angiogenesis and intraplaque hemorrhage It reduced macrophage infiltration in the lesions by modulating CCL2 and VCAM1 expression. Basic fibroblast growth factor (bFGF) is involved in the pathogenesis of atherosclerosis[3] and especially in the regulation of processes that drive plaque instability[4,5]. It is a known regulator of angiogenesis, macrophage infiltration as well as smooth muscle cells (SMCs) fate[6,7]. Intraplaque angiogenesis and inflammation are strongly connected in atherosclerosis and form a vicious cycle that drives the atherosclerotic plaque toward an unstable phenotype and possibly rupture
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