Abstract 16353: miR-10 Regulates Angiogenesis through VEGF Signaling Titration
Formation and remodeling of the vasculature during normal development and disease involves a highly conserved and precisely regulated network of attractants and repellants. Various signaling molecules and their corresponding receptors control the behavior of endothelial cells, but the post-transcriptional dose titration of these signals or their corresponding receptors by miRNAs is poorly understood. Here we describe a so far unrecognized role for the highly conserved miRNA family encoding miR-10 in modulating the behavior of endothelial cells during angiogenesis by modulating pro-angiogenic signaling. We found that knockdown of miR-10 in zebrafish resulted in premature truncation of intersegmental vessel growth in vivo in the trunk of zebrafish larvae. Furthermore, reduced miR-10 function in isolated human endothelial cells led to severely impaired angiogenic behavior in response to VEGF. We found that miR-10 functions, in part, by directly regulating the level of the cell-surface protein sequestering VEGF, fms-related tyrosine kinase 1 (FLT1), and his soluble splice variant sFLT1. Decreased miR-10 levels consequently led to increased FLT1 and sFLT1 levels negatively titrating angiogenic signaling mediated by KDR and thereby inhibiting angiogenesis. Our study provides novel insights into how angiogenic signaling is titrated in a miRNA-mediated manner on the basis of modulating the level of an important high affinity VEGF receptor, FLT1, and provides a potential target for the selective modulation of angiogenesis.
- © 2012 by American Heart Association, Inc.