Diabetes induces apoptosis and reduces the function of endothelial cells (EC) and endothelial progenitor cells (EPC). As a result, post-ischemic reparative angiogenesis and vasculogenesis are both impaired in diabetic subjects.1-12 The consequences are harmful: In the leg, severe microangiopathy aggravates atherosclerosis-induced muscular ischemia, thus contributing to gangrene and cutaneous ulcers with a severely impaired healing potential, which make amputation of the diabetic foot an all-too-frequent necessity.13,14 A remedy to prevent and treat such diabetic microvascular complications is urgently needed.
Neurotrophins (NTs) have been extensively studied for their actions on the nervous system. However, it is becoming increasingly evident that the expression and function of NTs is also important in the cardiovascular system. Both EC and EPC express tropomyosin kinase receptors (trk), which are tyrosine-kinases binding NTs with high affinity. The NT nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), acting on trkA and trkB respectively, promote EC survival and angiogenesis.3,15-18 Moreover, NGF, via trkA, is an autocrine survival factor for cardiomyocytes.19 NTs have another receptor of 75 KD MW (p75NTR). p75NTR contains a death domain and belongs to the TNF receptor super-family, but it does not bind TNF-α. In neural cells, p75NTR mediates apoptosis and cell cycle arrest.20-22 It was proposed that p75NTR has a low affinity for mature NTs, as it preferentially binds pro-forms of NTs.23-25 However, the mechanisms underpinning p75NTR activation and downstream molecular signaling have not been fully elucidated. Notably, no investigation of the role of p75NTR on EC and EPC survival and function or on blood vessel growth has been attempted to date. We previously reported that p75NTR is scarce in capillary EC of healthy murine limb muscles, but that expression strikingly increases following induction of type-1 diabetes and hindlimb ischemia; two conditions that also promote EC apoptosis.3,10,26
This study demonstrates that p75NTR promotes apoptosis of EC and vascular progenitor cells and inhibits neovascularization. We explain the anti-angiogenic effect of p75NTR by its inhibitory effect on the vascular endothelial growth factor A (VEGF-A)/Akt kinase axis. Finally, we provide evidence that p75NTR is responsible for the impaired neovascularization response to peripheral ischemia in diabetes.