title: The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway.
abstract: 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.
authors.affiliation: Department of Biology, Centre for Advanced Research in Environmental Genomics (CAREG), University of Ottawa, Ottawa, ON, Canada.
authors.forename: Shahram
authors.initials: S
authors.lastname: Eisa-Beygi
authors.forename: Gary
authors.initials: G
authors.lastname: Hatch
authors.forename: Sandra
authors.initials: S
authors.lastname: Noble
authors.forename: Marc
authors.initials: M
authors.lastname: Ekker
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Moon
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin; D002543:Cerebral Hemorrhage / Q000196:embryology / Q000473:pathology; D054022:Cerebrum / Q000098:blood supply* / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D051379:Mice; D060172:Morpholinos / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis; D054876:Prenylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D060172:Morpholinos; D011106:Polyisoprenyl Phosphates; D011758:Pyrroles; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate