Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
J Clin Invest. 2011 Jun;121(6):2278-89. doi: 10.1172/JCI46322. Epub 2011 May 23.
Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the number and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability to modulate the vascular response after injury.
血管生成素-1/Tek 信号是血管发育的关键调节因子，由于血管缺陷，常规敲除小鼠的血管生成素-1 或 Tek 会导致胚胎致死。此外，血管生成素-1 被认为是成熟血管稳定性所必需的。我们使用 Cre-Lox 条件性基因靶向方法研究了血管生成素-1 在胚胎和成年血管中的作用。我们在这里报告，血管生成素-1 对于调节发育中的血管的数量和直径是至关重要的，但对于周细胞募集是不需要的。心脏特异性敲除血管生成素-1 重现了常规敲除的表型，表明早期血管异常是由依赖于血流的缺陷引起的。引人注目的是，在 E13.5 天后整个胚胎中的缺失没有立即产生血管表型。然而，当与损伤或微血管应激结合时，血管生成素-1 缺乏导致严重的器官损伤、加速的血管生成和纤维化。这些发现重新定义了我们对血管生成素-1 的生物学作用的理解：它在静止的血管中是可有可无的，但在损伤后具有强大的调节血管反应的能力。
