Spontaneous intracranial hemorrhage is a debilitating form of stroke, often leading to death or permanent cognitive impairment. Many of the causative genes and the underlying mechanisms implicated in developmental cerebral-vascular malformations are unknown. Recent in vitro and in vivo studies in mice have shown inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway to be effective in stabilizing cranial vessels. Using a combination of pharmacological and genetic approaches to specifically inhibit the HMGCR pathway in zebrafish (Danio rerio), we demonstrate a requirement for this metabolic pathway in developmental vascular stability. Here we report that inhibition of HMGCR function perturbs cerebral-vascular stability, resulting in progressive dilation of blood vessels, followed by vessel rupture, mimicking cerebral cavernous malformation (CCM)-like lesions in humans and murine models. The hemorrhages in the brain are rescued by prior exogenous supplementation with geranylgeranyl pyrophosphate (GGPP), a 20-carbon metabolite of the HMGCR pathway, required for the membrane localization and activation of Rho GTPases. Consistent with this observation, morpholino-induced depletion of the β-subunit of geranylgeranyltransferase I (GGTase I), an enzyme that facilitates the post-translational transfer of the GGPP moiety to the C-terminus of Rho family of GTPases, mimics the cerebral hemorrhaging induced by the pharmacological and genetic ablation of HMGCR. In embryos with cerebral hemorrhage, the endothelial-specific expression of cdc42, a Rho GTPase involved in the regulation of vascular permeability, was significantly reduced. Taken together, our data reveal a metabolic contribution to the stabilization of nascent cranial vessels, requiring protein geranylgeranylation acting downstream of the HMGCR pathway.

译文

:自发性颅内出血是中风的一种虚弱形式,通常会导致死亡或永久性认知障碍。涉及发展性脑血管畸形的许​​多致病基因和潜在机制尚不清楚。最近在小鼠中进行的体外和体内研究表明,抑制3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)途径可有效稳定颅骨血管。使用药理和遗传学方法的组合来特异性抑制斑马鱼(Danio rerio)中的HMGCR途径,我们证明了这种代谢途径在发育性血管稳定性中的需求。在这里我们报道抑制HMGCR功能扰乱脑血管稳定性,导致血管进行性扩张,继而血管破裂,在人和鼠模型中模仿脑海绵状畸形(CCM)样病变。可以通过事先外源补充geranylgeranyl焦磷酸(GGPP)(HMGCR途径的20个碳代谢物)进行膜定位和激活Rho GTPases来挽救脑部出血。与该观察结果一致,吗啉代诱导的香叶基香叶基转移酶I(GGTase I)的β亚基耗竭,该酶有助于将GGPP部分翻译后转移至GTPases Rho家族的C末端,从而模拟脑出血由HMGCR的药理和遗传消融诱导。在患有脑出血的胚胎中,参与血管通透性调节的Rho GTPase cdc42的内皮特异性表达显着降低。综上所述,我们的数据揭示了新陈代谢对稳定新生颅血管的作用,需要在HMGCR途径下游作用的蛋白香叶基香叶基化作用。

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