Nox4, Poldip2 and vascular function

Abstract

NADPH oxidases (Nox) are expressed in all layers of the vessel wall and are integral to vascular physiology. Of particular interest is Nox4, which regulates vascular smooth muscle differentiation and vessel relaxation, but also has pathophysiological roles. Our laboratory has shown that polymerase delta interacting protein 2 (Poldip2) can increase the activity of Nox4. The Nox4/Poldip2 axis plays a role in cell proliferation and migration via its ability to regulate focal adhesion turnover and actin oxidation. However, Poldip2 has multiple binding partners and many additional effects on vascular pathology and physiology. Heterozygous Poldip2 mice have stiffer arteries, a reduced capacity to generate arterial force and increased collagen deposition. In addition, Poldip2 heterozygous mice have a reduced inflammatory response after ischemia in the hindlimb or following transient middle cerebral artery occlusion, which results in defective collateral formation in the hindlimb, but protection from aneurysm formation and reduced edema following stroke. The inhibition of edema results from a lack of disruption of the endothelial barrier and confers some neuroprotection. Overall, Poldip2, in part via Nox4 activity, plays a critical role in vascular physiology and pathology.