During vascular development, a branched structure of progressively smaller blood vessels is produced via processes such as vessel sprouting and splitting. Arteriovenous malformations (AVMs) are vascular defects that have been linked to mutations in RASA1, a Ras GTPase activating protein upstream of the MEK/ERK pathway. However, the mechanisms underpinning AVM formation are unclear. Here, Jasper Greysson-Wong, Sarah Childs and colleagues generate a zebrafish rasa1−/− model and show that these mutants develop an AVM in the caudal venous plexus (CVP) of their tails. Blood flow velocity is reduced in the AVM and expression of flow-responsive transcription factors is diminished compared with wild type. Altering blood flow by pharmacologically manipulating heart rate does not rescue the AVM defect, suggesting that changes to blood flow are a consequence, rather than a cause, of AVM formation. At the cellular level, rasa1−/− fish show signs of incomplete vessel splitting. Compared with wild type, the mutants also exhibit higher levels of active ERK in the caudal vein and increased vein cell size, and the authors find that inhibition of MEK is sufficient to rescue the AVM defect. Overall, this work suggests that depletion of RASA1 promotes MEK/ERK upregulation in vein cells to drive AVM formation.
No vein no gain: a venous origin for blood vessel defects Free
No vein no gain: a venous origin for blood vessel defects. Development 15 September 2023; 150 (18): e150_e1801. doi:
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