title: Aplexone targets the HMG-CoA reductase pathway and differentially regulates arteriovenous angiogenesis.
abstract: Arterial and venous endothelial cells exhibit distinct molecular characteristics at early developmental stages. These lineage-specific molecular programs are instructive to the development of distinct vascular architectures and physiological conditions of arteries and veins, but their roles in angiogenesis remain unexplored. Here, we show that the caudal vein plexus in zebrafish forms by endothelial cell sprouting, migration and anastomosis, providing a venous-specific angiogenesis model. Using this model, we have identified a novel compound, aplexone, which effectively suppresses venous, but not arterial, angiogenesis. Multiple lines of evidence indicate that aplexone differentially regulates arteriovenous angiogenesis by targeting the HMG-CoA reductase (HMGCR) pathway. Treatment with aplexone affects the transcription of enzymes in the HMGCR pathway and reduces cellular cholesterol levels. Injecting mevalonate, a metabolic product of HMGCR, reverses the inhibitory effect of aplexone on venous angiogenesis. In addition, aplexone treatment inhibits protein prenylation and blocking the activity of geranylgeranyl transferase induces a venous angiogenesis phenotype resembling that observed in aplexone-treated embryos. Furthermore, endothelial cells of venous origin have higher levels of proteins requiring geranylgeranylation than arterial endothelial cells and inhibiting the activity of Rac or Rho kinase effectively reduces the migration of venous, but not arterial, endothelial cells. Taken together, our findings indicate that angiogenesis is differentially regulated by the HMGCR pathway via an arteriovenous-dependent requirement for protein prenylation in zebrafish and human endothelial cells.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Choi
authors.forename: Kevin
authors.initials: K
authors.lastname: Mouillesseaux
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Wang
authors.forename: Hannah D G
authors.initials: HD
authors.lastname: Fiji
authors.forename: Sape S
authors.initials: SS
authors.lastname: Kinderman
authors.forename: Georg W
authors.initials: GW
authors.lastname: Otto
authors.forename: Robert
authors.initials: R
authors.lastname: Geisler
authors.forename: Ohyun
authors.initials: O
authors.lastname: Kwon
authors.forename: Jau-Nian
authors.initials: JN
authors.lastname: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D004625:Embryo, Nonmammalian; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013379:Substrate Specificity / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014680:Veins / Q000187:drug effects* / Q000502:physiology; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013449:Sulfonamides; C557896:aplexone; D006903:Hydroxymethylglutaryl CoA Reductases