Department of Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
J Cell Biol. 2013 Apr 29;201(3):449-65. doi: 10.1083/jcb.201209077.
Basic mechanisms by which cellular barriers sense and respond to integrity disruptions remain poorly understood. Despite its tenuous structure and constitutive exposure to disruptive strains, the vascular endothelium exhibits robust barrier function. We show that in response to micrometer-scale disruptions induced by transmigrating leukocytes, endothelial cells generate unique ventral lamellipodia that propagate via integrins toward and across these "micro-wounds" to close them. This novel actin remodeling activity progressively healed multiple micro-wounds in succession and changed direction during this process. Mechanical probe-induced micro-wounding of both endothelia and epithelia suggests that ventral lamellipodia formed as a response to force imbalance and specifically loss of isometric tension. Ventral lamellipodia were enriched in the Rac1 effectors cortactin, IQGAP, and p47Phox and exhibited localized production of hydrogen peroxide. Together with Apr2/3, these were functionally required for effective micro-wound healing. We propose that barrier disruptions are detected as local release of isometric tension/force unloading, which is directly coupled to reactive oxygen species-dependent self-restorative actin remodeling dynamics.
细胞屏障感知和响应完整性破坏的基本机制仍知之甚少。尽管血管内皮的结构脆弱，且经常受到破坏，但它仍具有强大的屏障功能。我们发现，在响应由穿过的白细胞引起的微米级破坏时，内皮细胞会产生独特的腹侧片状伪足，这些片状伪足通过整合素向并穿过这些“微伤口”传播，以封闭它们。这种新的肌动蛋白重塑活性可连续地逐渐愈合多个微伤口，并在此过程中改变方向。机械探针诱导的内皮细胞和上皮细胞的微创伤表明，腹侧片状伪足的形成是对力不平衡的反应，特别是等长张力的丧失。腹侧片状伪足富含 Rac1 效应物 cortactin、IQGAP 和 p47Phox，并表现出局部产生的过氧化氢。与 Apr2/3 一起，这些对于有效修复微伤口是必需的。我们提出，屏障破坏被检测为等长张力/力卸载的局部释放，这与依赖于活性氧的自我修复肌动蛋白重塑动力学直接相关。
