Li Song, Moon James Jaehyun, Miao Hui, Jin Gang, Chen Benjamin P C, Yuan Suli, Hu Yingli, Usami Shunichi, Chien Shu
Department of Bioengineering, University of California, Berkeley, CA 92093, USA.
J Vasc Res. 2003 Jul-Aug;40(4):378-88. doi: 10.1159/000072702. Epub 2003 Jul 29.
The interaction of vascular smooth muscle cells (SMCs) and extracellular matrix plays important roles in vascular remodeling. We investigated the signaling pathways involved in SMC-induced matrix contraction and SMC migration in three-dimensional (3D) collagen matrix. Matrix contraction is inhibited by the disruption of actin filaments but not microtubules. Therefore, we investigated the roles of signaling pathways related to actin filaments in matrix contraction. SMC-induced matrix contraction was markedly blocked (-80%) by inhibiting the Rho-p160ROCK pathway and myosin light chain kinase, and was decreased to a lesser extent (30-40%) by a negative mutant of Rac and inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase) or p38 mitogen-activated protein kinase (MAPK), but it was not affected by the inhibition of Ras and Cdc42-Wiskott-Aldrich syndrome protein (WASP) pathways. Inhibition of extracellular-signal-regulated kinase (ERK) decreased SMC-induced matrix contraction by only 15%. The migration speed and persistence of SMCs in the 3D matrix were decreased by the inhibition of p160ROCK, PI 3-kinase, p38 MAPK or WASP to different extents, and p160ROCK inhibitor had the strongest inhibitory effect. Our results suggest that the SMC-induced matrix contraction and the migration of SMCs in 3D matrix share some signaling pathways leading to force generation at cell-matrix adhesions and that various signaling pathways have different relative importance in the regulations of these processes in SMCs.
血管平滑肌细胞（SMC）与细胞外基质的相互作用在血管重塑中发挥着重要作用。我们研究了三维（3D）胶原基质中SMC诱导的基质收缩和SMC迁移所涉及的信号通路。肌动蛋白丝的破坏可抑制基质收缩，但微管破坏则无此作用。因此，我们研究了与肌动蛋白丝相关的信号通路在基质收缩中的作用。通过抑制Rho-p160ROCK通路和肌球蛋白轻链激酶，SMC诱导的基质收缩明显受阻（-80%），而Rac的负性突变体以及磷脂酰肌醇3激酶（PI 3激酶）或p38丝裂原活化蛋白激酶（MAPK）抑制剂可使其收缩程度较小地降低（30-40%），但Ras和Cdc42-威斯科特-奥尔德里奇综合征蛋白（WASP）通路的抑制对其无影响。细胞外信号调节激酶（ERK）的抑制仅使SMC诱导的基质收缩降低15%。在3D基质中，p160ROCK、PI 3激酶、p38 MAPK或WASP的抑制在不同程度上降低了SMC的迁移速度和持续性，其中p160ROCK抑制剂的抑制作用最强。我们的结果表明，SMC诱导的基质收缩和SMC在3D基质中的迁移共享一些导致细胞-基质黏附处产生力的信号通路，并且各种信号通路在SMC中这些过程的调节中具有不同的相对重要性。
