CELL-ADHESION MOLECULES AND INSULIN-LIKE GROWTH-FACTOR-I IN VASCULAR-DISEASE

Purpose: Recent advances in the understanding of the biologic mechanis ms of vascular diseases suggest that multifactorial stimulation of the endothelial cell and its subsequent adhesion to leukocytes is a prere quisite to the formation of atherosclerotic and restenotic lesions. As leukocyte-endothelial cell interaction is coordinated by a variety of cell adhesion molecules (CAMs), we hypothesized that the expression o f certain CAMs is upregulated in the vasculature of patients who have peripheral vascular disease. In addition, we proposed that insulin-lik e growth factor-1 (IGF-1) increases monocyte-endothelial adhesion by m eans of upregulation of these CAMs. Methods: Using immunohistochemical techniques, the expression of intracellular adhesion molecule-1 (ICAM -1), vascular cell adhesion molecule-1(VCAM-1), E-selectin, and P-sele ctin was examined in human vascular disease specimens. Normal aortas o btained from the organ retrieval system were studied as control specim ens. Adhesion studies between human umbilical vein endothelial cells ( HUVECs) incubated with IGF-1 and purified human blood monocytes labele d with (51)chromium were completed. Western blotting and flow cytometr y were performed to show CAM expression on IGF-l-treated HUVECs. Resul ts: Of the CAMs, ICAM-1, P-selectin, and E-selectin were distinctly in creased in diseased specimens when compared with control specimens (p < 0.05). Adhesion studies showed an increase in monocyte-endothelial c ell adhesion of as much as 40% to 45% (p < 0.01) over baseline, with p eak adherence occurring 4 hours after treatment with IGF-1. IGF-1 incr eased adherence in a dose- and time-dependent manner. The threshold co ncentration of IGF-1 that induced increased adhesion was 20 ng/ml, wit h a maximum effect occurring at 150 ng/ml. This increased adhesion was attenuated by pretreatment with IGF-I receptor antibody, as well as w ith genistein and herbimycin-A, which are potent and selective tyrosin e kinase inhibitors. Increased adhesion correlated with an increase in the expression of CAMs on the surface of the HUVECs. An additive effe ct on adhesion was observed between IGF-1 and tumor necrosis factor-al pha (TNF-alpha) and endothelin-1 (ET-1). Finally, immunohistochemical analysis of human vascular disease specimens revealed an increased exp ression of IGF-1 receptors as compared with control specimens (p < 0.0 5). Conclusions: These results suggest that IGF-1 may be important in the pathogenesis of peripheral vascular disease by increasing endothel ial cell-monocyte adhesion by means of an increase in the expression o f ICAM-1 and VCAM-1.