ZFIN ID: ZDB-PUB-121206-44
The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway
Eisa-Beygi, S., Hatch, G., Noble, S., Ekker, M., and Moon, T.W.
Date: 2013
Source: Developmental Biology   373(2): 258-266 (Journal)
Registered Authors: Eisa-Beygi, Shahram, Ekker, Marc, Hatch, Gary
Keywords: HMGCR, vasculature, prenylation, zebrafish, statin, cdc42
MeSH Terms:
  • Alkyl and Aryl Transferases/metabolism
  • Animals
  • Atorvastatin
  • Cerebral Hemorrhage/embryology
  • Cerebral Hemorrhage/pathology
  • Cerebrum/blood supply*
  • Cerebrum/drug effects
  • Cerebrum/embryology*
  • Cerebrum/metabolism
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/enzymology
  • Embryo, Nonmammalian/pathology
  • Endothelial Cells/drug effects
  • Endothelial Cells/enzymology
  • Endothelial Cells/pathology
  • Heptanoic Acids/pharmacology
  • Hydroxymethylglutaryl CoA Reductases/metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
  • Mice
  • Morpholinos/pharmacology
  • Polyisoprenyl Phosphates/biosynthesis
  • Prenylation*/drug effects
  • Pyrroles/pharmacology
  • Signal Transduction*/drug effects
  • Zebrafish/embryology*
  • cdc42 GTP-Binding Protein/metabolism
  • rhoA GTP-Binding Protein/metabolism
PubMed: 23206891 Full text @ Dev. Biol.

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.