Greysson-Wong Jasper, Rode Rachael, Ryu Jae-Ryeon, Chan Jo Li, Davari Paniz, Rinker Kristina D, Childs Sarah J
Alberta Children's Hospital Research Institute, University of Calgary, 3330 University Drive NW, Calgary, AB T2N 4N1, Canada.
Department of Biochemistry and Molecular Biology, University of Calgary, 3330 University Drive NW, Calgary, AB T2N 4N1, Canada.
Development. 2023 Sep 15;150(18). doi: 10.1242/dev.201820. Epub 2023 Sep 14.
Arteriovenous malformations (AVMs) develop where abnormal endothelial signalling allows direct connections between arteries and veins. Mutations in RASA1, a Ras GTPase activating protein, lead to AVMs in humans and, as we show, in zebrafish rasa1 mutants. rasa1 mutants develop cavernous AVMs that subsume part of the dorsal aorta and multiple veins in the caudal venous plexus (CVP) - a venous vascular bed. The AVMs progressively enlarge and fill with slow-flowing blood. We show that the AVM results in both higher minimum and maximum flow velocities, resulting in increased pulsatility in the aorta and decreased pulsatility in the vein. These hemodynamic changes correlate with reduced expression of the flow-responsive transcription factor klf2a. Remodelling of the CVP is impaired with an excess of intraluminal pillars, which is a sign of incomplete intussusceptive angiogenesis. Mechanistically, we show that the AVM arises from ectopic activation of MEK/ERK in the vein of rasa1 mutants, and that cell size is also increased in the vein. Blocking MEK/ERK signalling prevents AVM initiation in mutants. Alterations in venous MEK/ERK therefore drive the initiation of rasa1 AVMs.
动静脉畸形（AVM）发生于异常的内皮信号传导导致动脉与静脉直接相连之处。Ras GTP酶激活蛋白RASA1的突变会导致人类出现AVM，正如我们所展示的，斑马鱼rasa1突变体也会出现这种情况。rasa1突变体形成海绵状AVM，其包含部分背主动脉和尾静脉丛（CVP，一种静脉血管床）中的多条静脉。这些AVM会逐渐扩大并充满缓慢流动的血液。我们发现，AVM导致最小和最大流速均升高，致使主动脉搏动性增加而静脉搏动性降低。这些血流动力学变化与血流反应性转录因子klf2a表达降低相关。CVP的重塑受到损害，腔内柱过多，这是不完全套入式血管生成的迹象。从机制上讲，我们发现AVM源于rasa1突变体静脉中MEK/ERK的异位激活，并且静脉中的细胞大小也增加。阻断MEK/ERK信号传导可防止突变体中AVM的起始。因此，静脉中MEK/ERK的改变驱动了rasa1 AVM的起始。
