Watson S, Burnside T, Carver W
Department of Developmental Biology and Anatomy, University of South Carolina School of Medicine, Columbia 29208, USA.
J Cell Physiol. 1998 Nov;177(2):224-31. doi: 10.1002/(SICI)1097-4652(199811)177:2<224::AID-JCP4>3.0.CO;2-P.
The accumulation and organization of extracellular matrix (ECM) components play critical roles in development, maintenance, and pathogenesis of most organ systems. These processes are regulated by the precisely orchestrated expression of ECM components, their receptors, and matrix proteases. The collagen gel culture system has been extensively used as a model to examine ECM remodeling similar to that which occurs during development and wound healing. Growth factors, including transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor, and angiotensin II, have been shown to stimulate collagen gel contraction. The present studies were undertaken to begin to examine the mechanisms through which angiotensin II stimulates collagen remodeling and gel contraction. These studies indicate that angiotensin II stimulates collagen gel contraction by isolated heart fibroblasts in a dose-dependent manner and that this response is inhibited by the AT1 receptor antagonist Losartan. Furthermore, stimulation of collagen gel contraction by angiotensin II is also blocked by the src-related tyrosine kinase inhibitors genistein and herbimycin, indicating that activation of tyrosine kinases plays critical roles in this process. Stimulation of gel contraction by angiotensin II also involves the activation of JAK2, a member of the JAK/STAT pathways of transcriptional activation. Immunoprecipitation of surface-labeled fibroblasts indicate that cell surface levels of collagen-binding integrins also increase in response to angiotensin II treatment. Determining the underlying mechanisms regulating ECM remodeling is essential to understanding the role of ECM organization in development and disease.
细胞外基质（ECM）成分的积累和组织在大多数器官系统的发育、维持和发病机制中起着关键作用。这些过程受ECM成分、其受体和基质蛋白酶精确协调的表达调控。胶原凝胶培养系统已被广泛用作模型，以研究类似于发育和伤口愈合过程中发生的ECM重塑。包括转化生长因子-β、血小板衍生生长因子、胰岛素样生长因子和血管紧张素II在内的生长因子已被证明能刺激胶原凝胶收缩。本研究旨在开始探讨血管紧张素II刺激胶原重塑和凝胶收缩的机制。这些研究表明，血管紧张素II以剂量依赖的方式刺激离体心脏成纤维细胞的胶原凝胶收缩，且这种反应被AT1受体拮抗剂氯沙坦抑制。此外，血管紧张素II对胶原凝胶收缩的刺激也被src相关酪氨酸激酶抑制剂染料木黄酮和除莠霉素阻断，表明酪氨酸激酶的激活在这一过程中起关键作用。血管紧张素II对凝胶收缩的刺激还涉及JAK2的激活，JAK2是转录激活的JAK/STAT途径的成员。对表面标记的成纤维细胞进行免疫沉淀表明，胶原结合整合素的细胞表面水平也会因血管紧张素II处理而增加。确定调节ECM重塑的潜在机制对于理解ECM组织在发育和疾病中的作用至关重要。
