bFGF blockade reduces intraplaque angiogenesis and macrophage infiltration in atherosclerotic vein graft lesions in ApoE3*Leiden mice

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.

On vasa vasorum: A history of advances in understanding the vessels of vessels

“…Thus, prevention of neovessel instability may prove therapeutic by markedly reducing the impact of vasa vasorum expansion. A small-molecule inhibitor of FGF2 represents another candidate for plaque stabilization due to its ability to reduce macrophage infiltration and intraplaque angiogenesis ( 130 ). A gene transfer strategy to deliver decoy VEGFRs to the adventitia of rabbit vessels implanted with bare metal stents prevented vasa vasorum neovascularization in stent restenosis ( 131 ).…”

Phosphorylcholine Monoclonal Antibody Therapy Decreases Intraplaque Angiogenesis and Intraplaque Hemorrhage in Murine Vein Grafts

“…For migration assays, HUVEC were seeded in 12-wells plate in complete medium and grown until 100% confluence [ 44 ]. To cause cell cycle arrest, cells were incubated in EBM-2 medium supplemented with 0.2% FBS and 24 h later, a scratch-wound was made.…”

Pro-angiogenic approach for skeletal muscle regeneration

“…A fine balance between pro-angiogenic and anti-angiogenic factors allows a balanced progression of the vascular system. When this balance is broken, angiogenesis is altered leading to pathological states including inflammation, tumour, and restenosis [40][41][42] . Tumours and metastases depend on a regular blood supply and the balance between pro-angiogenic and anti-angiogenic factors shifted in favour of increased angiogenesis in this disease.…”