Involvement of the Fibroblast Growth Factor System in Adaptive and Chemokine-Induced Arteriogenesis

Abstract

Abstract-Fibroblast growth factors (FGFs) have been applied in a variety of therapeutic and experimental studies to improve collateral blood flow. However, the pathophysiological role and the temporospatial expression of the FGFs and their receptors during arteriogenesis have never been elucidated in vivo. Here, we report that collateral artery growth in its early phase is associated with an increased expression of FGF receptor-1 (FGFR-1) and syndecan-4 on mRNA and protein levels as well as with an increased kinase activity of FGFR-1 in a rabbit model of arteriogenesis. However, the mRNA levels of FGF-1 and -2 remained constant. Our data suggest that these growth factors are supplied by endothelial attracted monocytes that, in turn, produce and deliver the FGFs to growing collateral arteries. Monocyte chemoattractant protein-1-stimulated arteriogenesis was strongly reduced in rabbits by application of the FGF inhibitor polyanetholesulfonic acid, indicating that the monocyte-related arteriogenesis (as well as the unstimulated adaptation proper) is promoted by FGFs. In summary, this study shows that arteriogenesis is associated with an increased expression of the FGFRs at the site of the vessel, whereas the growth-promoting ligands are supplied by monocytes in a paracrine way. Key Words: arteriogenesis Ⅲ fibroblast growth factors Ⅲ fibroblast growth factor receptor-1 Ⅲ syndecan-4 Ⅲ monocytes C ollateral artery growth (arteriogenesis) occurs spontaneously as an adaptive response to vascular occlusion. However, the speed of growth can be stimulated by factors such as monocyte chemoattractant protein-1 (MCP-1), 1 transforming growth factor-␤1, 2 or granulocyte-macrophage colony-stimulating factor, 3,4 which either attract or prolong the lifespan of monocytes. In a variety of studies, fibroblast growth factors (FGFs) have also been applied for their potency to induce vascular growth and to promote the recovery of blood flow after arterial occlusion.The FGFs are a family of Ͼ20 polypeptides that mediate a broad range of biological activities (hematopoiesis, development, and wound repair) in a variety of cell types of mesenchymal and neuroectodermal origin. These activities are initiated through 4 structurally related membraneassociated tyrosine kinase FGF receptors (FGFRs) that are derived from separate genes and exist in a multitude of isoforms. 5 Ligand-induced dimerization of these high-affinity receptors, which is mediated by low-affinity receptors, is a key event in transmembrane signaling. It leads to an increase in kinase activity, resulting in the autophosphorylation of the receptor and the induction of diverse biological responses. 6 -8 Special attention is focused on FGF-1 and FGF-2, potent mitogens playing an important role in cell proliferation, migration, and differentiation. 9 -11 These FGFs differ from most of the other FGFs because they lack hydrophobic signal peptides and therefore are concentrated within their cell of origin. 12 Exogenously administrated, these growth factors have been shown to incr...

Gelatin Hydrogel Microspheres Enable Pinpoint Delivery of Basic Fibroblast Growth Factor for the Development of Functional Collateral Vessels

“…5,[13][14][15][16][17]24 Therefore, the growth factor used for therapy should have a potent effect to induce arteriogenesis to acquire large-conductance collateral vessels, although induction of vasculogenesis and/or angiogenesis might also be advantageous. It was shown by Deindl et al 18 that bFGF plays an important role during adaptive arteriogenesis, and it also promotes angiogenesis in ischemic tissues. 15,16 We thus believe that bFGF is one of the most suitable growth factors for angiogenic therapy.…”

“…4 Our strategy was to develop functional collateral vessels by lodging bFGF-impregnated AGHMs in the peripheral part of the donor artery through IA administration. Trapped in small arterioles, AGHMs are expected to slowly release bFGF, a potent stimulator of arteriogenesis, 15,16,18 thereby inducing large-conductance arteries with sufficient blood inflow toward the ischemic tissue.…”

Physical Activity in the Prevention and Treatment of Coronary Artery Disease

“…Further remodeling in response to long‐term exercise training involves the expression of cytokines and growth factors (eg, vascular endothelial growth factor A, transforming growth factor ß, platelet‐derived growth factor, fibroblast growth factors 1 and 2, and insulin‐like growth factor), which leads to the proliferation and growth of endothelial cells and smooth muscle cells and ultimately drives the arteriolarization of capillaries2, 43, 44, 45, 46 (Figure 2). In the trained heart, the consequence is unaltered capillary density, but there is a larger and more profound arterial supply 2, 47.…”

Myocardial Salvage Through Coronary Collateral Growth by Granulocyte Colony-Stimulating Factor in Chronic Coronary Artery Disease

“…But it documented for the first time, as far as we are aware, the efficacy of G-CSF with regard to the function of collateral vessels. Aside from G-CSF, there have been well-investigated substances with arteriogenic efficacy such as monocyte chemoattractant protein-1 23 ; another colony-stimulating factor, granulocytemonocyte CSF (GM-CSF); 24 transforming growth factor ␤1 25 ; fibroblast growth factors 26 ; tumor necrosis factor ␣ 27 ; and matrix metalloproteinases. 28 Among these, only colonystimulating factors have been investigated for clinical use in coronary or peripheral artery disease, whereby GM-CSF has been shown to be effective in the former but not the latter condition.…”