Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
J Cell Biol. 2011 Jun 27;193(7):1305-19. doi: 10.1083/jcb.201011143.
Pericytes migrate to nascent vessels and promote vessel stability. Recently, we reported that secreted protein acidic and rich in cysteine (SPARC)-deficient mice exhibited decreased pericyte-associated vessels in an orthotopic model of pancreatic cancer, suggesting that SPARC influences pericyte behavior. In this paper, we report that SPARC promotes pericyte migration by regulating the function of endoglin, a TGF-β1 accessory receptor. Primary SPARC-deficient pericytes exhibited increased basal TGF-β1 activity and decreased cell migration, an effect blocked by inhibiting TGF-β1. Furthermore, TGF-β-mediated inhibition of pericyte migration was dependent on endoglin and αV integrin. SPARC interacted directly with endoglin and reduced endoglin interaction with αV integrin. SPARC deficiency resulted in endoglin-mediated blockade of pericyte migration, aberrant association of endoglin in focal complexes, an increase in αV integrins present in endoglin immunoprecipitates, and enhanced αV integrin-mediated activation of TGF-β. These results demonstrate that SPARC promotes pericyte migration by diminishing TGF-β activity and identify a novel function for endoglin in controlling pericyte behavior.
周细胞向新生血管迁移并促进血管稳定。最近，我们报道了在胰腺癌的原位模型中，缺乏分泌蛋白酸性富含半胱氨酸（SPARC）的小鼠表现出周细胞相关血管减少，这表明 SPARC 影响周细胞行为。在本文中，我们报告 SPARC 通过调节转化生长因子-β1 辅助受体 endoglin 的功能来促进周细胞迁移。原代 SPARC 缺陷周细胞表现出基础 TGF-β1 活性增加和细胞迁移减少，这一效应可被抑制 TGF-β1 阻断。此外，TGF-β 介导的周细胞迁移抑制依赖于 endoglin 和 αV 整合素。SPARC 与 endoglin 直接相互作用，并减少 endoglin 与 αV 整合素的相互作用。SPARC 缺陷导致 endoglin 介导的周细胞迁移阻断、焦点复合物中 endoglin 的异常聚集、内源性 endoglin 免疫沉淀中存在的 αV 整合素增加以及增强的 αV 整合素介导的 TGF-β 激活。这些结果表明，SPARC 通过降低 TGF-β 活性促进周细胞迁移，并确定了 endoglin 在控制周细胞行为中的新功能。
