Endothelial growth factors differentially regulate leukocyte recruitment

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are angiogenic cytokines frequently produced at sites of inflammation. Previously, we demonstrated that bFGF enhances leukocyte recruitment and endothelial cell adhesion molecule (CAM) expression during inflammation. Here, we investigated whether VEGF may also modulate these parameters. Inflammation was induced in skin of Lewis rats by i.d. injection of inflammatory stimuli ± VEGF ± bFGF. Migration of 51 Cr‐monocytes and 111 In‐PMN to the dermal lesions and 125 I‐anti‐CAM mAb plus 131 I‐isotype control IgG binding to the dermal vasculature were quantitated after 2 hours of inflammation. VEGF slightly enhanced the TNF‐α induced recruitment of monocytes by 39±16% (p<0.05), and increased P‐selectin, E‐selectin and ICAM‐1 expression by 2–3 fold over TNF‐α alone (p<0.05). However recruitment of monocytes to TNF‐α + IFN‐γ and of PMN to all stimuli tested was not affected by VEGF. In contrast, bFGF enhanced recruitment of both leukocyte types to all stimuli (by 35 to 132%). bFGF, but not VEGF, increased the chemotactic activity for PMN in TNF‐α + IFN‐γ exudates by 54% (p<0.001). Co‐treatment of dermal sites with VEGF + bFGF increased the recruitment of PMN in response to TNF‐α or TNF‐α + IFN‐γ significantly more than with each growth factor alone. However, the CAM expression or chemotactic activity did not correlate with this increase, suggesting that additional mechanisms are involved. Thus bFGF and VEGF differentially enhance leukocyte recruitment to inflammatory stimuli, but they have an additive or synergistic effect, depending on the stimulus. Supported by IWK fellowship and CIHR.