Endothelial Cell-Specific ROS Production Increases Susceptibility to Aortic Dissection
Background—Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states but therapeutic strategies remain limited by incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelial specific Nox2 over-expression and tested the susceptibility to aortic dissection following Angiotensin II infusion.
Methods and Results—A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Angiotensin II mediated aortic dissection that was never observed in Wt mice. Nox2 Tg aortas had increased endothelial ROS production, endothelial VCAM-1 expression, MMP activity and CD45+ inflammatory-cell infiltration. Conditioned media from Nox2 Tg ECs induced greater Erk1/2 phosphorylation in VSMCs compared to Wt controls through secreted Cyclophilin A (CypA). Nox2 Tg ECs (but not VSMCs) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in VSMC Erk1/2 phosphorylation conferred by EC conditioned media and pre-incubation with CypA augmented Ang II induced VSMC ROS production.
Conclusions—These findings demonstrate a pivotal role for EC-derived ROS in the determination of susceptibility of the aortic wall to Ang II mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signalling mechanism through which EC ROS regulates susceptibility of structural components of the aortic wall to aortic dissection.
- Received July 16, 2013.
- Revision received April 7, 2014.
- Accepted April 14, 2014.