Functioning of an arteriovenous fistula requires heme oxygenase-2.

Heme oxygenase-2 (HO-2), the constitutive isoform of the heme-degrading enzyme heme oxygenase, may serve as an anti-inflammatory vasorelaxant, in part, by generating carbon monoxide. Arteriovenous fistulas (AVFs) are employed as hemodialysis vascular accesses because they provide an accessible, high-blood-flow vascular segment. We examined the role of vascular expression of HO-2 in AVF function. An AVF was created in mice by anastomosing the carotid artery to the jugular vein. HO-2 expression was detected by immunohistochemistry in the intact carotid artery, mainly in endothelial cells and smooth muscle cells; expression of HO-2 protein and mRNA was modestly increased in the artery of the AVF. Creating an AVF in HO-2(-/-) mice compared with an AVF in HO-2(+/+) mice led to markedly reduced AVF blood flow and increased numbers of nonfunctioning AVFs. The impairment of AVF function in the setting of HO-2 deficiency could not be ascribed to either preexisting intrinsic abnormalities in endothelium-dependent and endothelium-independent relaxation of the carotid artery in HO-2-deficient mice or to impaired vasorelaxant responses in the intact carotid artery in vivo. HO-1 mRNA was comparably induced in the AVF in HO-2(+/+) and HO-2(-/-) mice, whereas the AVF in HO-2(-/-) mice compared with that in HO-2(+/+) mice exhibited exaggerated induction of matrix metalloproteinase (MMP)-9 but similar induction of MMP-2. HO-2 deficiency also led to lower AVF blood flow when AVFs were created in uremia, the latter induced by subtotal nephrectomy. We conclude that HO-2 critically contributes to the adequacy of AVF blood flow and function.