Identification of Padi2 as a novel angiogenesis-regulating gene by genome association studies in mice

• DOI: 10.1371/journal.pgen.1006848
• Publication Date: 2017-06-15T16:38:52Z
• Authors: Mehrdad Khajavi; Yi Zhou; Amy E. Birsner; Lauren Bazinet; Amanda Rosa Di Sant; Alex J. Schiffer; Michael S. Rogers; Subrahmanian Tara...; Bella Hu; Vy Nguyen; Leonard Zon; Robert J. D’Amato
• Keywords: Candidate gene

Recent findings indicate that growth factor-driven angiogenesis is markedly influenced by genetic variation. This variation in angiogenic responsiveness may alter the susceptibility to a number of angiogenesis-dependent diseases. Here, we utilized diversity available common inbred mouse strains identify loci and candidate genes responsible for differences response. The corneal micropocket neovascularization assay was performed on 42 different using basic fibroblast factor (bFGF) pellets. We genome-wide association study utilizing efficient mixed-model (EMMA) mapping induced vessel area from all strains. Our analysis yielded five with significance chromosomes 4, 8, 11, 15 16. further refined chromosome 4 within haplotype block containing multiple genes. These were evaluated expression corneas various vitro functional assays human microvascular endothelial cells (HMVECs). Of these, found peptidyl arginine deiminase type II (Padi2), known be involved metabolic pathways, have strong correlation shared high In addition, inhibition Padi2 demonstrated dosage-dependent effect HMVECs. To investigate its role vivo, knocked down transgenic kdrl:zsGreen zebrafish embryos morpholinos. had disrupted formation compared control siblings. impaired vascular pattern partially rescued PADI2 mRNA, providing evidence specificity morphant phenotype. Taken together, our first potential as an angiogenesis-regulating gene. characterization other associated pathways provide new understanding regulation novel targets diagnosis treatment wide variety