Endothelial NFκB-Dependent Regulation of Arteriogenesis and Branching
Background—Arteriogenesis and collateral formation are complex processes requiring integration of multiple inputs to coordinate vessel branching, growth, maturation and network size. Factors regulating these processes have not been determined.
Methods and Results—We used a dominant-negative IκBαSR construct under control of an endothelial-specific inducible promoter to selectively suppress endothelial NFκB activation during development or in the adult vasculature or in vitro. Inhibition of NFκB activation resulted in formation of an excessively branched arterial network that was composed of immature vessels and provided poor distal tissue perfusion. Molecular analysis demonstrated reduced adhesion molecules expression leading to decreased monocyte influx, reduced HIF-1α levels and a marked decrease in Dll4 expression with a consequent decrease in Notch signaling. The latter was the principal cause of increased vascular branching, as treatment with Jagged-1 peptide reduced the size of arterial network to baseline levels.
Conclusions—These findings identify NFκB as a key regulator of adult and developmental arteriogenesis and collateral formation. NFκB achieves this by regulating HIF1α-dependent expression of VEGF-A and PDGF-BB that are necessary for development and maturation of the arterial collateral network and by regulating Dll4 expression that in turn determines the network's size and complexity.
- Received May 21, 2012.
- Accepted October 10, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited