Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3 and Glial-Derived Neurotrophic Factor Enhance Angiogenesis in a Tissue-EngineeredIn VitroModel

Abstract

Skin is a major source of secretion of the neurotrophic factors nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and glial-derived neurotrophic factor (GDNF) controlling cutaneous sensory innervation. Beside their neuronal contribution, we hypothesized that neurotrophic factors also modulate the cutaneous microvascular network. First, we showed that NGF, BDNF, NT-3, and GDNF were all expressed in the epidermis, while only NGF and NT-3 were expressed by cultured fibroblasts, and BDNF by human endothelial cells. We demonstrated that these peptides are highly potent angiogenic factors using a human tissue-engineered angiogenesis model. A 40% to 80% increase in the number of capillary-like tubes was observed after the addition of 10 ng/mL of NGF, 0.1 ng/mL of BDNF, 15 ng/mL of NT-3, and 50 ng/mL of GDNF. This is the first characterization of the direct angiogenic effect of NT-3 and GDNF. This angiogenic effect was mediated directly through binding with the neurotrophic factor receptors tropomyosin-receptor kinase A (TrkA), TrkB, GFRa-1 and c-ret that were all expressed by human endothelial cells, while this effect was blocked by addition of the Trk inhibitor K252a. Thus, if NGF, BDNF, NT-3, and GDNF may only moderately regulate the microvascular network in normal skin, they might have the potential to greatly increase angiogenesis in pathological situations.

Pronerve Growth Factor Induces Angiogenesis via Activation of TrkA: Possible Role in Proliferative Diabetic Retinopathy

“…Previous studies showed that Trk receptors play a key role in mediating the mitogenic and angiogenic response of neurotrophins including NGF and BDNF [17, 25, 26]. Our previous work demonstrated significant upregulation of p75 NTR receptor expression in clinical and experimental diabetes [11, 27].…”

“…NGF activates two different receptors including the high affinity tropomyosin-related receptor A (TrkA), which is a tyrosine kinase, and the low affinity p75 NTR neurotrophin receptors (p75 NTR ) [16]. Previous studies demonstrated that the angiogenic response of NGF was mediated via activation of TrkA [15, 17, 18]. …”

Sustained Delivery of VEGF Maintains Innervation and Promotes Reperfusion in Ischemic Skeletal Muscles Via NGF/GDNF Signaling

“…40 Our results also correlate with recent findings of a GNDF role in skin de novo blood vessel formation, also supporting signaling interactions between the neural and vascular systems. 41 Thus, NGF and GDNF, having similar effects on perfusion recovery of the ischemic limbs, may act via different signaling cascades in endothelial cells.…”

In vitro glycation of an endothelialized and innervated tissue-engineered skin to screen anti-AGE molecules

“…They also induce ECM stiffening following direct proteins cross-linking [53]. In addition, most of these processes are interconnected, sensory nerves enhancing keratinocyte proliferation and angiogenesis through neuropeptides release, while keratinocytes support the nerve network maintenance by neurotrophic factors secretion, which are also angiogenic [54].…”

“…However, we observed that CML formation may decrease over time, probably because of a natural protein turnover, necessitating a continuous glycation to maintain AGE expression. To complete the model, we incorporated endothelial cells to build a capillary-like network as previously described [46,54], enabling the analysis of the impact of glycation on angiogenesis. Sensory neurons obtained from mice embryos were finally incorporated in the model to form a sensory nerve network as previously shown [40].…”