Nguyen Ha-Long, Boon Laurence M, Vikkula Miikka
Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium.
Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Centre, Saint Luc University Hospital, 1200 Brussels, Belgium.
Hum Mol Genet. 2023 Jan 6;32(2):276-289. doi: 10.1093/hmg/ddac169.
Somatic activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations have been reported in patients with arteriovenous malformations. By producing LSL-Kras (G12D); Cdh5 (PAC)-CreERT2 [iEC-Kras (G12D*)] mice, we hoped to activate KRAS within vascular endothelial cells (ECs) to generate an arteriovenous malformation mouse model. Neonatal mice were treated daily with tamoxifen from postnatal (PN) days 1-3. Mortality and phenotypes varied amongst iEC-Kras (G12D*) pups, with only 31.5% surviving at PN14. Phenotypes (focal lesions, vessel dilations) developed in a consistent manner, although with unpredictable severity within multiple soft tissues (such as the brain, liver, heart and brain). Overall, iEC-Kras (G12D*) pups developed significantly larger vascular lumen areas compared with control littermates, beginning at PN8. We subsequently tested whether the MEK inhibitor trametinib could effectively alleviate lesion progression. At PN16, iEC-Kras (G12D*) pup survival improved to 76.9%, and average vessel sizes were closer to controls than in untreated and vehicle-treated mutants. In addition, trametinib treatment helped normalize iEC-Kras (G12D*) vessel morphology in PN14 brains. Thus, trametinib could act as an effective therapy for KRAS-induced vascular malformations in patients.
在患有动静脉畸形的患者中已报道存在体细胞激活的 Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）突变。通过培育 LSL-Kras（G12D）；Cdh5（PAC）-CreERT2 [iEC-Kras（G12D*）]小鼠，我们希望在血管内皮细胞（ECs）内激活 KRAS 以生成动静脉畸形小鼠模型。新生小鼠在出生后（PN）第 1 - 3 天每天用他莫昔芬处理。iEC-Kras（G12D*）幼崽的死亡率和表型各不相同，在 PN14 时只有 31.5%存活。表型（局灶性病变、血管扩张）以一致的方式出现，尽管在多个软组织（如脑、肝、心和脑）中的严重程度不可预测。总体而言，从 PN8 开始，iEC-Kras（G12D*）幼崽与对照同窝小鼠相比，发育出明显更大的血管腔面积。我们随后测试 MEK 抑制剂曲美替尼是否能有效缓解病变进展。在 PN16 时，iEC-Kras（G12D*）幼崽的存活率提高到 76.9%，并且平均血管大小比未治疗和用载体处理的突变体更接近对照。此外，曲美替尼治疗有助于使 PN14 脑内 iEC-Kras（G12D*）血管形态正常化。因此，曲美替尼可作为治疗患者 KRAS 诱导的血管畸形的有效疗法。
