Nerve Growth Factor Promotes Endothelial Progenitor Cell-Mediated Angiogenic Responses

Jadhao, Chandrakala S.; Bhatwadekar, Ashay D.; Jiang, Youde; Boulton, Michael E.; Steinle, Jena J.; Grant, Maria B.

doi:10.1167/iovs.11-8430

Cited by 22 publications

(28 citation statements)

References 45 publications

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“…Our results lend further support to a recent study showing that the angiogenic effect of proNGF in cancer cells is exerted mainly via TrkA rather than p75 NTR receptor [41]. The inhibitory effect of K252a, staurosporine-related compound [42], on angiogenic response have been demonstrated in several studies [14, 15, 18, 25, 36–38], nevertheless, we believe that our results are the first to demonstrate involvement of TrkA activation in response to proNGF in retinal endothelial cells. …”

Section: Discussionsupporting

confidence: 89%

“…Therefore, it is conceivable that the previously reported increases in NGF are mixed proNGF/NGF rather than NGF alone. So far, researchers have focused on studying angiogenic response of NGF in retinal endothelial cells [18, 25, 36–38]; however, until now no studies have evaluated the possible angiogenic action of proNGF. Therefore, we tested the hypothesis that accumulated proNGF contributes to angiogenic response elicited by ocular fluids from PDR patients.…”

Section: Discussionmentioning

confidence: 99%

“…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]. …”

Section: Introductionmentioning

confidence: 99%

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

Elshaer

Abdelsaid

Al-Azayzih³

et al. 2013

Journal of Diabetes Research

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Proliferative diabetic retinopathy (PDR) is the leading cause of blindness in working age Americans. We demonstrated that diabetes disturbs the homeostasis of nerve growth factor (NGF) resulting in accumulation of its precursor proNGF. Increases in proNGF were positively correlated with progression of diabetic retinopathy, having the highest level in ocular fluids from PDR patients compared to nondiabetic patients. Here, we attempted to evaluate the contribution and the possible mechanism of proNGF to PDR. The angiogenic response of aqueous humor samples from PDR patients was examined in human retinal endothelial cells in the presence or absence of anti-proNGF antibody. Additional cultures were treated with mutant-proNGF in the presence of specific pharmacological inhibitors of TrkA and p75NTR receptors. PDR-aqueous humor samples exerted significant angiogenic response including cell proliferation, migration, and alignment into tube-like structures. These effects were significantly reduced by anti-proNGF antibody but not by IgG. Treatment of retinal endothelial cells with mutant-proNGF activated phosphorylation of TrkA and p38MAPK; however, it did not alter p75NTR expression. Inhibition of TrkA but not p75NTR significantly reduced mutant-proNGF-induced cell proliferation, cell migration, and tube formation. Taken together, these results provide evidence that proNGF can contribute to PDR at least in part via activation of TrkA.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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

Elshaer

Abdelsaid

Al-Azayzih³

et al. 2013

Journal of Diabetes Research

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“…Angiogenesis plays a significant role in tendon healing, and stimulating neovascular formations can promote tendon regeneration . Several studies have reported that the nervous system influences angiogenesis via cell‐to‐cell interactions or through secretion of various signaling neural‐cytokines . Herein, it was found that ruptured Achilles tendon tissue was surrounded by nerve‐derived cells that scattered into and around the ruptured wound site.…”

Section: Discussionmentioning

confidence: 90%

Neural crest‐derived cells migrate from nerve to participate in Achilles tendon remodeling

Pan

Qiu

et al. 2018

Wound Repair Regeneration

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During tendon injury, nerve ingrowth is one of the earliest events of tendon repair and remodeling. Since peripheral neurons and associated cells are mostly derived from neural crest (NC) cells, we sought to investigate the role of NC-derived cells in tendon regeneration. Thus, we used Sox10-Cre/ROSA26-Flox-Red Fluorescent Protein (RFP) transgenic mice to trace these cells during tendon regeneration. After 4 weeks of Achilles tendon rupture, the injured tendon tissues were harvested for immunohistological analyses, cell isolation, and phenotype identification. In addition, the tenocytes were co-cultured with RFP labeled cells to examine cellular functions. Following the injury, a significant number of RFP-labeled cells penetrated into the wound site and reached a peak (∼30% of cells) after 2 weeks, and then stabilized at a level of approximately 20%. Interestingly, 36.9% RFP labeled cells in the injured area expressed Tuj1, suggesting that most of the cells are peripheral neurons. Some RFP /Tuj1 cells were also found adjacent to newly formed blood vessels in the tendon. Importantly, the existing neuropeptide Y (NPY) and neuropeptide Y receptor (NPYr) in the invading nerve and blood vessels were directly correlated. In addition, there were also RFP cells (∼30%) negative for neuronal markers but positive for fibroblast markers, that is, FAP (34.7%) and Vimentin (Vmt) (27.2%), and approximately 10% positive for Sox10. Indeed, many RFP cells isolated from the ruptured Achilles tendon showed long spindle shapes and expressed fibroblast phenotypic markers FSP1 and FAP. Part of the Sox10 RFP-labeled cells exhibited osteogenic and adipogenic differentiation ability. It is concluded that after Achilles tendon injury, nerves sprout into the wound site. The NC-derived Vmt /FAP mesenchymal cells and peripheral nerves participate in tendon regeneration.

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“…NGF contributes to retinal neovascularization in the oxygen-induced retinopathy mouse model by TrkA activation, which is attenuated by inhibition of Trk receptors [88]. NGF has also been shown to activate TrkA receptor on CD34 + endothelial progenitor cells, stimulating their angiogenic behavior [89]. NTs can induce angiogenesis by acting directly on Trkexpressing endothelial cells and on subsets of Trk-expressing bone marrow-derived hematopoietic cells or indirectly via induction of pro-angiogenic factors, such as VEGF [90,91].…”

Section: Role Of Prongf/ngf In Ischemic Neovascularizationmentioning

confidence: 99%

Nerve growth factor in diabetic retinopathy: beyond neurons

Mysona¹,

Shanab²,

Elshaer³

et al. 2014

Expert Review of Ophthalmology

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Diabetic retinopathy (DR), a major ocular complication of diabetes, is a leading cause of blindness in US working age adults with limited treatments. Neurotrophins (NTs), a family of proteins essential for growth, differentiation and survival of retinal neurons, have emerged as potential players in the pathogenesis of DR. NTs can signal through their corresponding tropomyosin kinase related receptor to mediate cell survival or through the p75 neurotrophin receptor with the co-receptor, sortilin, to mediate cell death. This review focuses on the role of NGF, the first discovered NT, in the development of DR. Impaired processing of proNGF has been found in ocular fluids from diabetic patients as well as experimental models. Evidence from literature and our studies support the notion that NTs appear to play multiple potential roles in DR, hence, understanding their contribution to DR may lead to promising therapeutic approaches for this devastating disease.

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Nerve Growth Factor Promotes Endothelial Progenitor Cell-Mediated Angiogenic Responses

Abstract: Our in vitro results suggest that NGF released from ischemic nerves in vivo may contribute to the "angiogenic switch" by stimulating the angiogenic behavior of CD34⁺ cells while minimally affecting resident retinal endothelial cells.

Cited by 22 publications

References 45 publications

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

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

Neural crest‐derived cells migrate from nerve to participate in Achilles tendon remodeling

Nerve growth factor in diabetic retinopathy: beyond neurons

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