The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway
- Authors
- Eisa-Beygi, S., Hatch, G., Noble, S., Ekker, M., and Moon, T.W.
- ID
- ZDB-PUB-121206-44
- 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.