Details

Autor(en) / Beteiligte

• Li, Ruofei
• Xiao, Xiao
• Yan, Yupeng
• Yu, Liang
• Lv, Cheng
• Zhang, Yu
• Hong, Tao
• Zhang, Hongqi
• Wang, Yibo

Titel

GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals

Ist Teil von

• Brain (London, England : 1878), 2024-04, Vol.147 (4), p.1571-1586

Ort / Verlag

England

Erscheinungsjahr

2024

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Arteriovenous malformations (AVMs) are fast-flow vascular malformations and refer to important causes of intracerebral haemorrhage in young adults. Getting deep insight into the genetic pathogenesis of AVMs is necessary. Herein, we identified two vital missense variants of G protein-coupled receptor (GPCR) associated sorting protein 1 (GPRASP1) in AVM patients for the first time and congruously determined to be loss-of-function variants in endothelial cells. GPRASP1 loss-of-function caused endothelial dysfunction in vitro and in vivo. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral haemorrhage, AVMs and exhibited vascular anomalies in multiple organs. GPR4 was identified to be an effective GPCR binding with GPRASP1 to develop endothelial disorders. GPRASP1 deletion activated GPR4/cAMP/MAPK signalling to disturb endothelial functions, thus contributing to vascular anomalies. Mechanistically, GPRASP1 promoted GPR4 degradation. GPRASP1 enabled GPR4 K63-linked ubiquitination, enhancing the binding of GPR4 and RABGEF1 to activate RAB5 for conversions from endocytic vesicles to endosomes, and subsequently increasing the interactions of GPR4 and ESCRT members to package GPR4 into multivesicular bodies or late endosomes for lysosome degradation. Notably, the GPR4 antagonist NE 52-QQ57 and JNK inhibitor SP600125 effectively rescued the vascular phenotype caused by endothelial Gprasp1 deletion. Our findings provided novel insights into the roles of GPRASP1 in AVMs and hinted at new therapeutic strategies.