Endothelial Cell Specific FGD5 Involvement in Vascular Pruning Defines Neovessel Fate in Mice
Background—New vessel formation contributes to organ development during embryogenesis and tissue repair in response to mechanical damage, inflammation and ischemia in adult organisms. Early angiogenesis includes formation of an excessive primitive network that needs to be reorganized into a secondary vascular network with higher hierarchical structure. Vascular pruning, the removal of aberrant neo-vessels by apoptosis, is a vital step in this process. Although multiple molecular pathways for early angiogenesis have been identified, little is known about the genetic regulators of secondary network development.
Methods and Results—Using a transcriptomics approach, we identified a new endothelial specific gene named FYVE, RhoGEF and PH domain-containing 5 (FGD5) that plays a crucial role in vascular pruning. Loss-and gain-of-function studies demonstrate that FGD5 inhibits neovascularization, indicated by in vitro tube-formation, aortic-ring and coated-bead assays, and by in vivo coated-bead plug assays and studies in the murine retina model. FGD5 promotes apoptosis-induced vaso-obliteration via induction of the hey1-p53 pathway by direct binding and activation of cdc42. Indeed, FGD5 correlates with apoptosis in ECs during vascular remodelling, and was linked to rising p21CIP1 levels in aging mice.
Conclusions—Here we have identified FGD5 as a novel genetic regulator of vascular pruning by activation of EC-targeted apoptosis.
- Received August 31, 2011.
- Accepted April 16, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited