The Role of Angiogenic Growth Factors in Arteriogenesis

Abstract

Background/Aims: Collateral vessels restore only about 40% of the maximum dilatory reserve after femoral artery occlusion, whereas complete normalization is reached by increased fluid shear stress (FSS). We studied the role of known potent angiogenic growth factors (separately or in combination) in arteriogenesis by determining their expression in FSS-stimulated collaterals and close-to-collateral infusion of growth factor peptides in a rabbit model of femoral artery occlusion. Methods: Values of maximum collateral conductance (C_max) and post mortem angiograms were compared to those achievable by high FSS. mRNA levels of growth factor ligands and receptors were determined in FSS-stimulated collaterals. Results: Seven days after vessel occlusion, FSS-stimulated legs showed a C_max not significantly different from that of not occluded femoral arteries. Arteriogenesis was significantly less enhanced after growth factor treatment (MCP-1 86%, Ad5.1-FGF-4 75%, bFGF 72%, PDGF 64%, VEGF 50% of C_max after FSS stimulation). RT-PCR showed no differential expression of FGF receptors, but an up-regulation of VEGF-receptor-2. Conclusion: The most potent known angiogenic growth factors at high pharmacological doses reach only a fraction of the maximum conductance obtained by high FSS. Arteriogenesis differs from angiogenesis, so the main focus to markedly improve arteriogenesis should be put on the underlying mechanisms of shear stress.

Fluid shear stress upregulates placental growth factor in the vessel wall via NADPH oxidase 4

“…FSS is inversely proportional to the cube of vessel diameter and rapidly decreases as the vessel wall expands. However, prolonged increased FSS achieved by arteriovenous shunt results in continued enlargement of collateral vessels (13,37,44,45). Recently, compelling clinical evidence for the role of FSS in arteriogenesis was provided by Gloekler et al (18).…”

Ischemia Impairs Vasodilation in Skeletal Muscle Resistance Artery

“…Unfortunately, the positive effect of VEGF on vascularization in animal models [10,28] has not been observed in large clinical trials [29]. In addition to a lack of efficacy, VEGF therapies are associated with edema, due to the ability of VEGF to increase endothelial permeability [19,24].…”

“…The most common ischemia models involve ligations and arteriovenous shunts, which can be used to assess revascularizations in the rabbit hindlimb [28]. Arteriovenous shunts involve the ligation of both femoral arteries and for the side-to-side anastomosis operation of the distal stump of the left femoral artery with the accompanying vein [26].…”

Heme Oxygenase 1 Is Differentially Involved in Blood Flow–Dependent Arterial Remodeling

“…MCP-1 is probably upregulated in the endothelium 33 and attracts monocytes/ macrophages, which are needed for flow-induced remodeling. 15 MCP-1 is a potent growth factor able to restore collateral conductance after femoral artery occlusion, 34 highlighting its role in arteriogenesis and remodeling after ischemia.…”