Peripheral artery disease (PAD) affects more than 200 million adults worldwide. Critical limb ischemia (CLI), the most advanced form of PAD, causes significant morbidity, mortality, and health care resource utilization. Despite our increased understanding of the pathobiology of PAD, medical treatments remain inadequate and revascularization (surgical and non-surgical) or amputation are unfortunately the major therapeutic options. Therefore, it is imperative to address this important unmet clinical need, potentially by the development of novel pharmacologic therapies combined with more effective management strategies. However, current efforts in these areas are significantly hindered due to incomplete knowledge of the fundamental mechanisms that govern the dysregulation of vascular function, as well as the failure to generate an effective vascular network to restore flow. Our recent observations have identified CCN3 (Nov), a specific member of the matricellular protein family, CCN (Cyr61, Ctgf, Nov), as an important regulator of endothelial function in the context of neovascularization. CCN3 expression was found to be strongly reduced in limb tissues from CLI patients. In a murine hind limb ischemia (HLI) model, global CCN3 deficiency resulted in enhanced necrosis concomitant with decreases in tissue reperfusion, hypoxia-induced factor (HIF) signaling and VEGF-A production - key mechanisms responsible for the loss of functional collateral blood flow in PAD. Additionally, cell-type specific deletion of CCN3 in mice and preliminary cell-based studies indicate that endothelial cell CCN3 deficiency plays a major role in the impairment of blood flow recovery. Restrictive deletion of CCN3 in the endothelium phenocopies the effects of the global CCN3 knockout. This strongly suggests that endothelial CCN3 is a positive regulator of collateral blood flow recovery following HLI. At the cellular level, loss of CCN3 results in impaired endothelial migration and tube formation, pivotal processes involved in angiogenesis requisite for blood flow recovery. Collectively, these observations led to the central hypothesis that CCN3 serves as a critical physiological regulator in driving neovascularization and the attendant tissue perfusion.
In Aim 1, we will fully characterize the role of CCN3 in the regulation of collateral blood flow.
Aim 2 is designed to elucidate the mechanisms by which CCN3 deficiency leads to compromised neovascularization and collateral blood flow. Finally, in Aim 3, we plan to explore the therapeutic potential of CCN3 in preclinical models of limb ischemia. The results of these studies will elucidate the role of CCN3 in controlling endothelial function in ischemia and the mechanisms underlying its ability to promote neovascularization and functional collateral blood flow.
The underlying molecular mechanisms that lead to the development of the clinical manifestations of (peripheral artery disease) PAD remain not fully elucidated. Studies in this proposal aim to characterize the role of CCN3 in the pathogenesis of PAD. Results gleaned from our studies may facilitate the development of novel therapies to ameliorate PAD progression.
