Vasa vasorum are important sources of oxygen and nutrients to vascular tissues and their proliferation influences the pathogenesis of arterial disease; however, the regulation of their growth is poorly understood partly because of a lack of appropriate experimental models. We cuffed common carotid arteries of rabbits with segments of the contralateral carotid artery, a procedure that resulted in rapid and extensive elaboration of adventitial vasa vasorum and connective tissue. Endothelium-lined microvessels were observed at 1 week but vessels as large as 300 microm with an organizing media were common by 3 weeks. These vasa vasorum arose primarily from the vascular supply to contiguous tissues, but also from the carotid artery. This angiogenesis was accompanied by increased expression of the angiogenic factor, vascular endothelial growth factor (VEGF), in the invading connective tissue cells and increased expression of the transcriptional regulator of VEGF, hypoxia-inducible factor-1alpha (HIF-1alpha), in these connective tissues and in the cuffing artery. These findings are consistent with the hypothesis that upregulation of HIF-1alpha and VEGF expression drives angiogenesis of vasa vasorum in this model. This simple model may be amenable to the study of the development and elaboration of vasa vasorum, especially in the context of vascular pathologies.