Thrombospondin-1 is a potent mitogen and chemoattractant for human vascular smooth muscle cells

被引:74
作者
Patel, MK
Lymn, JS
Clunn, GF
Hughes, AD
机构
[1] Department of Clinical Pharmacology, Imperial College School of Medicine, St Mary's Hospital
关键词
thrombospondin-1; DNA synthesis; proliferation; migration; human vascular smooth muscle;
D O I
10.1161/01.ATV.17.10.2107
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Thrombospondin-1 (TSP-1) is a matricellular protein that is present in negligible amounts in normal human vasculature but occurs in significant amounts in diseased vessels. In this study, we examined the effect of TSP-1 on DNA synthesis, proliferation, and migration in human vascular smooth muscle cells grown from saphenous vein. TSP-1 (0.1 to 30 mu g/mL) elicited a concentration-dependent increase in DNA synthesis under serum-free conditions. In combination with platelet-derived growth factor, TSP-1 induced a synergistic effect on DNA synthesis that was significantly higher than the additive effect of both agents. In proliferation assays, TSP-1 increased cell numbers by 50% relative to the serum-free controls over 14 days. In migration assays, conducted using modified Boyden chambers, TSP-1 (greater than or equal to 10 mu g/mL) elicited marked chemotaxis to a degree equivalent to platelet-derived growth factor. The chemotactic response to TSP-1 (10 mu g/mL) was abolished by the GRGDSP peptide but unaffected by the control GRGESP peptide, whereas neither peptide inhibited DNA synthesis stimulated by TSP-1. Inhibition of tyrosine kinase activity with genistein or tyrphostin A23 abolished DNA synthesis induced by TSP-1, and a neutralizing antibody to platelet-derived growth factor had no effect on DNA synthesis. Similarly, migration in response to TSP-1 was largely inhibited by these tyrosine kinase inhibitors. TSP-1 is a strong mitogen and chemoattractant for human vascular smooth muscle cells under serum-free conditions. The novel finding that TSP-1 is mitogenic for human cells contrasts with previous studies that have not shown any significant effect of TSP-1 itself on the growth of animal-derived smooth muscle cells. TSP-1 may play an important modulatory role in the local regulation of vascular smooth muscle function in vascular pathologies in humans.
引用
收藏
页码:2107 / 2114
页数:8
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