Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12432-7. doi: 10.1073/pnas.1304188110. Epub 2013 Jul 9.
Endothelial dysfunction is associated with diverse cardiovascular pathologies. Here, we show a previously unappreciated role for the Abelson (Abl) family kinases (Abl and Arg) in endothelial function and the regulation of angiogenic factor pathways important for vascular homeostasis. Endothelial Abl deletion in Arg-null mice led to late-stage embryonic and perinatal lethality, with mutant mice displaying focal loss of vasculature and tissue necrosis. Loss of Abl kinases led to increased endothelial cell apoptosis both in vitro and in vivo, contributing to vascular dysfunction, infarction, and tissue damage. Mechanistically, we identify a unique dual role for Abl kinases in the regulation of angiopoietin/Tie2 protein kinase signaling. Endothelial Abl kinases modulate Tie2 expression and angiopoietin-1-mediated endothelial cell survival. These findings reveal a critical requirement for the Abl kinases in vascular development and function, which may have important implications for the clinical use of Abl kinase inhibitors.
内皮功能障碍与多种心血管病理有关。在这里，我们展示了阿贝尔（Abl）家族激酶（Abl 和 Arg）在血管内皮功能和血管稳态重要的血管生成因子途径调节中的一个以前未被认识到的作用。Arg 基因缺失的内皮细胞 Abl 缺失导致晚期胚胎和成体致死，突变小鼠表现出血管和组织坏死的局灶性丧失。Abl 激酶的缺失导致体外和体内内皮细胞凋亡增加，导致血管功能障碍、梗死和组织损伤。从机制上讲，我们发现 Abl 激酶在血管生成素/Tie2 蛋白激酶信号转导的调节中具有独特的双重作用。内皮 Abl 激酶调节 Tie2 表达和血管生成素-1 介导的内皮细胞存活。这些发现揭示了 Abl 激酶在血管发育和功能中的关键需求，这可能对 Abl 激酶抑制剂的临床应用具有重要意义。
