Use Of Vascular Endothelial Growth Factor Research Articles

Risk Factors and VEGF, hs-CRP, and ESR in Central Serous Chorioretinopathy.

This study aimed to investigate the risk factors associated with central serous chorioretinopathy (CSC) and analyze the relationship between vascular endothelial growth factor (VEGF), high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and CSC. A total of 109 patients diagnosed with CSC (CSC group) at our ophthalmology clinic from February 2017 to February 2021 were included, with 103 volunteers from our hospital's health examination center serving as the control group. Additionally, the new multimodal imaging classification of 109 CSC patients was further divided into simple CSC (57 cases) and complex CSC (52 cases). Demographic data, underlying diseases, medical history, and medication history were collected. Levels of VEGF, hs-CRP, and ESR were measured, and multifactorial logistic regression analysis was performed to identify factors influencing CSC. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic value of VEGF, hs-CRP, and ESR in CSC. The CSC group showed a higher proportion of males, smoking history, alcohol consumption, comorbid obstructive sleep apnea, hypothyroidism, renal disease, Helicobacter pylori infection, steroid use, and shift work compared to the control group (P < 0.05). VEGF, hs-CRP, and ESR levels were significantly higher in the CSC group than in the control group (P < 0.05). The levels of VEGF, hs-CRP, and ESR in the complex CSC group were higher than those in the simple CSC group (P < 0.05). Male gender, shift work, Helicobacter pylori infection, hypothyroidism, elevated VEGF, hs-CRP, and ESR were identified as risk factors for CSC (P < 0.05). The combined diagnostic value of VEGF, hs-CRP, and ESR (area under the ROC curve: 0.886) was higher than that of individual markers (0.722, 0.728, and 0.703, respectively) (P < 0.05). Male gender, shift work, Helicobacter pylori infection, hypothyroidism, and elevated levels of VEGF, hs-CRP, and ESR are risk factors for CSC. The combined use of VEGF, hs-CRP, and ESR demonstrates higher diagnostic efficiency in identifying CSC.

Hydroxyapatite (HA) scaffold supplemented with VEGF and BMP-2 growth factors enhanced osteogenic proliferation and differentiation of MC3T3-E1 cells

Background: Engineered bone tissue, made up of hydroxyapatite (HA) scaffold is the current alternative in bone transplant. The scaffold needs to mimic the extracellular matrix (ECM) to support bone growth and repair. Vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP-2) are vital in producing a suitable ECM environment to promote bone regeneration. Objective: To elucidate the synergistic effect of VEGF and BMP-2 growth factors on MC3T3-E1 osteoblast cells. Method: MC3T3-E1 cells were cultured in vitro and seeded onto a HA scaffold supplied with VEGF and BMP-2 growth factors. The characterisation of its mineralisation was evaluated on Day three and Day seven using the Alizarin Red staining (ARS) technique. Result: Positive ARS staining was observed in the HA scaffold supplied with VEGF and BMP-2 growth factors in vitro, thus indicating that a high level of calcium was deposited. These results suggest that the combined use of VEGF and BMP-2 will increase cell proliferation and osteoblast differentiation in vitro. Conclusion: Therefore, the synergistic effects of VEGF and BMP-2-loaded HA scaffold confirm the process as a promising approach to enhance the osteogenic effect and support cellular functions of osteoblastic cells in bone tissue engineering applications.

Отдельные аспекты применения ингибиторов VEGF в лечении ретинопатии недоношенных

Nowadays increasing use of VEGF (vascular endothelial growth factor) inhibitors in the ROP (retinopathy of prematurity) treatment, undergoing clinical trials in Russian Federation, as well as the widely VEGF inhibitors off-label using, make this review higly relevant. In this work it was possible to reflect some significant aspects of the VEGF inhibitors application in the ROP treatment, which the researchers focus on. Evaluating the effectiveness of VEGF inhibitors in the treatment of ROP in zone II (stage 3+), bevacizumab therapy and retinal laser coagulation proved to be effective. The use of 0.2 mg of ranibizumab is more effective compared to laser treatment in patients with ROP stage 3+. Analysis of the treatment effectiveness of ROP in zone I (stages 1+, 2+, 3+) showed that ranibizumab is more effective than retinal laser coagulation (68% and 61%, respectively), however, without statistically significant differences. Results of surgical treatment of ROP indicate its high efficiency at stage 4a. There are limited data, according to the results, the combination of vitrectomy with the introduction of VEGF inhibitors leads to a faster regression of the disease. Data on the systemic effects of VEGF inhibitors available in the literature are contradictory, which requires further study of this problem. Key words: retinopathy of prematurity, VEGF inhibitors, literature review

Effect of Extracellular Ribonucleic Acids on Neurovascularization in Osteoarthritis.

Osteoarthritis is a degenerative disease characterized by abnormal neurovascularization at the osteochondral junctions, the regulatory mechanisms of which remain poorly understood. In the present study, a murine osteoarthritic model with augmented neurovascularization at the osteochondral junction is used to examine this under-evaluated facet of degenerative joint dysfunction. Increased extracellular RNA (exRNA) content is identified in neurovascularized osteoarthritic joints. It is found that the amount of exRNA is positively correlated with the extent of neurovascularization and the expression of vascular endothelial growth factor (VEGF). In vitro binding assay and molecular docking demonstrate that synthetic RNAs bind to VEGF via electrostatic interactions. The RNA-VEGF complex promotes the migration and function of endothelial progenitor cells and trigeminal ganglion cells. The use of VEGF and VEGFR2 inhibitors significantly inhibits the amplification of the RNA-VEGF complex. Disruption of the RNA-VEGF complex by RNase and polyethyleneimine reduces its in vitro activities, as well as prevents excessive neurovascularization and osteochondral deterioration in vivo. The results of the present study suggest that exRNAs may be potential targets for regulating nerve and blood vessel ingrowth under physiological and pathological joint conditions.

Do intravitreal anti-vascular endothelial growth factor agents lead to renal adverse events? A pharmacovigilance real-world study.

Intravitreal vascular endothelial growth factor (VEGF) blockade is essential in many macular edema diseases treatment. However, intravitreal VEGF treatment has been reported to lead to deteriorated proteinuria and renal function. This study aimed to explore the relationship between renal adverse events (AEs) and the intravitreal use of VEGF inhibitors. In the FDA's Adverse Event Reporting System (FAERS) database, we searched for renal AEs of patients receiving various anti-VEGF drugs. We performed statistics on renal AEs in patients treated with Aflibercept, Bevacizumab, Ranibizumab, and Brolucizumab (from January 2004 to September 2022) using disproportionate and Bayesian analysis. We also investigated the time to onset, fatality, and hospitalization rates of renal AEs. We identified 80 reports. Renal AEs were most frequently associated with Ranibizumab (46.25%) and Aflibercept (42.50%). However, the association between intravitreal anti-VEGFs and renal AEs was insignificant since the reporting odds ratio of Aflibercept, Bevacizumab, Ranibizumab, and Brolucizumab were 0.23 (0.16, 0.32), 0.24 (0.11, 0.49), 0.37 (0.27, 0.51) and 0.15 (0.04, 0.61), respectively. The median time to renal AEs onsets was 37.5 (interquartile range 11.0-107.3) days. The hospitalization and fatality rates in patients who developed renal AEs were 40.24 and 9.76%, respectively. There are no clear signals for the risk of renal AEs following various intravitreal anti-VEGF drugs based on FARES data.

Neuroprotective Effects of VEGF in the Enteric Nervous System.

Although the enteric nervous system (ENS) functions largely autonomously as part of the peripheral nervous system (PNS), it is connected to the central nervous system (CNS) via the gut–brain axis. In many neurodegenerative diseases, pathological changes occur in addition to gastrointestinal symptoms, such as alpha-synuclein aggregates in Parkinson’s disease, which are found early in the ENS. In both the CNS and PNS, vascular endothelial growth factor (VEGF) mediates neuroprotective and neuroregenerative effects. Since the ENS with its close connection to the microbiome and the immune system is discussed as the origin of neurodegenerative diseases, it is necessary to investigate the possibly positive effects of VEGF on enteric neurons. Using laser microdissection and subsequent quantitative RT-PCR as well as immunohistochemistry, for the first time we were able to detect and localize VEGF receptor expression in rat myenteric neurons of different ages. Furthermore, we demonstrate direct neuroprotective effects of VEGF in the ENS in cell cultures. Thus, our results suggest a promising approach regarding neuroprotection, as the use of VEGF (may) prevent neuronal damage in the ENS.

In vitro modulation of Schwann cell behavior by VEGF and PDGF in an inflammatory environment

Peripheral glial cell transplantation with Schwann cells (SCs) is a promising approach for treating spinal cord injury (SCI). However, improvements are needed and one avenue to enhance regenerative functional outcomes is to combine growth factors with cell transplantation. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) are neuroprotective, and a combination of these factors has improved outcomes in rat SCI models. Thus, transplantation of SCs combined with VEGF and PDGF may further improve regenerative outcomes. First, however, we must understand how the two factors modulate SCs. In this in vitro study, we show that an inflammatory environment decreased the rate of SC-mediated phagocytosis of myelin debris but the addition of VEGF and PDGF (alone and combined) improved phagocytosis. Cytokine expression by SCs in the inflammatory environment revealed that addition of PDGF led to significantly lower level of pro-inflammatory cytokine, TNF-α, but IL-6 and anti-inflammatory cytokines (TGF-β and IL-10), remained unaltered. Further, PDGF was able to decrease the expression of myelination associated gene Oct6 in the presence of inflammatory environment. Overall, these results suggest that the use of VEGF and/or PDGF combined with SC transplantation may be beneficial in SCI therapy.

Metabolic and conformational stabilization of a VEGF-mimetic beta-hairpin peptide by click-chemistry.

HPLW is a Vascular Endothelial Growth Factor (VEGF)-mimicking beta-hairpin peptide endowed of proangiogenic effect and showing valuable biomedical application in the proangiogenic therapy. However, the translational potential of HPLW is limited by its low metabolic stability, which would shorten the invivo efficacy of the molecule. Here, we developed a peptide analog of HPLW, named HPLW2, that retains the structural and biological properties of the original peptide but features an impressive resistance to degradation by human serum proteases. HPLW2 was obtained by covalently modifying the chemical structure of the peptide with molecular tools known to impart protease resistance. Notably, the peptide was cyclized by installing an interstrand triazole bridge through Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reaction. HPLW2 appears as a novel and promising drug candidate with potential biomedical application in the proangiogenic therapy as a low molecular weight drug, alternative to the use of VEGF. Our work points out the utility of the interstrand triazole bridge as effective chemical platform for the conformational and metabolic stabilization of beta-hairpin bioactive peptides.

Vascular endothelial growth factor (VEGF) targeting therapy for persistent, recurrent, or metastatic cervical cancer.

Vascular endothelial growth factor (VEGF) targeting therapy for persistent, recurrent, or metastatic cervical cancer.

Diagnostic Value of VEGF-A, VEGFR-1 and VEGFR-2 in Feline Mammary Carcinoma.

Vascular endothelial growth factor (VEGF-A) plays an essential role in tumor-associated angiogenesis, exerting its biological activity by binding and activating membrane receptors, as vascular endothelial growth factor receptor 1 and 2 (VEGFR-1, VEGFR-2). In this study, serum VEGF-A, VEGFR-1, and VEGFR-2 levels were quantified in 50 cats with mammary carcinoma and 14 healthy controls. The expression of these molecules in tumor-infiltrating lymphocytes (TILs) and in cancer cells was evaluated and compared with its serum levels. Results obtained showed that serum VEGF-A levels were significantly higher in cats with HER2-positive and Triple Negative (TN) Normal-Like subtypes, when compared to control group (p = 0.001, p = 0.020). Additionally, serum VEGFR-1 levels were significantly elevated in cats presenting luminal A, HER2-positive and TN Normal-Like tumors (p = 0.011, p = 0.048, p = 0.006), as serum VEGFR-2 levels (p = 0.010, p = 0.046, p = 0.005). Moreover, a positive interaction was found between the expression of VEGF-A, VEGFR-1, and VEGFR-2 in TILs and their serum levels (p = 0.002, p = 0.003, p = 0.003). In summary, these findings point to the usefulness of VEGF-A and its serum receptors assessment in clinical evaluation of cats with HER2-positive and TN Normal-Like tumors, suggesting that targeted therapies against these molecules may be effective for the treatment of these animals, as described in human breast cancer.

2-deoxy-d-ribose (2dDR) upregulates vascular endothelial growth factor (VEGF) and stimulates angiogenesis

BackgroundDelayed neovascularisation of tissue-engineered (TE) complex constructs is a major challenge that causes their failure post-implantation. Although significant progress has been made in the field of angiogenesis, ensuring rapid neovascularisation still remains a challenge. The use of pro-angiogenic agents is an effective approach to promote angiogenesis, and vascular endothelial growth factor (VEGF) has been widely studied both at the biological and molecular levels and is recognised as a key stimulator of angiogenesis. However, the exogenous use of VEGF in an uncontrolled manner has been shown to result in leaky, permeable and haemorrhagic vessels. Thus, researchers have been actively seeking alternative agents to upregulate VEGF production rather than exogenous use of VEGF in TE systems. We have previously revealed the potential of 2-deoxy-d-ribose (2dDR) as an alternative pro-angiogenic agent to induce angiogenesis and accelerates wound healing. However, to date, there is not any clear evidence on whether 2dDR influences the angiogenic cascade that involves VEGF. MethodsIn this study, we explored the angiogenic properties of 2dDR either by its direct application to human aortic endothelial cells (HAECs) or when released from commercially available alginate dressings and demonstrated that when 2dDR promotes angiogenesis, it also increases the VEGF production of HAECs. ResultsThe VEGF quantification results suggested that VEGF production by HAECs was increased with 2dDR treatment but not with other sugars, including 2-deoxy-l-ribose (2dLR) and d-glucose (DG). The stability studies demonstrated that approximately 40–50% of the 2dDR had disappeared in the media over 14 days, either in the presence or absence of HAECs, and the reduction was higher when cells were present. The concentration of VEGF in the media also fell after day 4 associated with the reduction in 2dDR. ConclusionThis study suggests that 2dDR (but not other sugars tested in this study) stimulates angiogenesis by increasing the production of VEGF. We conclude 2dDR appears to be a practical and effective indirect route to upregulating VEGF for several days, leading to increased angiogenesis.

Vascular endothelial growth factor for in vivo bone formation: A systematic review.

BackgroundTo achieve optimal bone formation one of the most influential parameters has been mentioned to be adequate blood supply. Vascular endothelial growth factor (VEGF) is hereby of particular interest in bone regeneration, because of its primary ability to induce neovascularization and chemokine affection for endothelial cells (EC), and is considered to be the main regulator of vascular formation. However, the growth factor has yet to be implemented in a clinical setting in orthopaedic intervention surgery. We hypothesised that the development of VEGF in vivo for bone formation in the last decade had progressed towards clinical application since the latest systematic review from 2008.ObjectiveThis systematic review recapped the last 13 years of in vivo bone regeneration using vascular endothelial growth factor (VEGF).MethodA total of 1374 articles were identified using the PubMed search string (vegf or “vascular endothelial growth factor”) and (osteogen∗ or “bone formation” or “bone regeneration”). By 3 selection phases 24 published articles were included by the criteria of being in vivo, using only VEGF for bone formation, published after 2007 and written in English. Articles in vitro, written in different languages than English and older than 2007 was excluded. The most recent systematic review on this subject was published in 2008, with the latest included study from 01 to 11-2007. All included studies were classified based on animal, type of defect, scaffold, control group, type of VEGF, release rate, dosage of VEGF, time of evaluation and results. Each study was evaluated for risk of bias by modified CAMARADES quality assessment for the use in experimental animal studies. The score was calculated by peer review journal publication, use of control group, randomisation of groups, justified VEGF dosage, blinding of results, details on animal model, sample size calculation, comply with ethics and no conflict of interest.ResultsNo clinical trials or human application studies were obtained from our search. Experimentally, 11 articles using solely VEGF for bone formation had a group or a timepoint significantly better than the corresponding control group. 18 articles revealed no significant difference of VEGF compared to the control group and 1 article reported a significant decreased bone growth using VEGF compared to control.ConclusionBased on these results no clinical studies have yet been performed. However, indications in the best use of VEGF from experimental studies could be made towards that the optimal release is within the first three weeks, in defect models, with the best effect before eight weeks. Future designs should incorporate this with standardised and reproducible models for verification towards clinical practice.The translational potential of this articleThis systematic review aims to assess the existing literature to focus on methodologies and outcomes that can provide future knowledge regarding the solitary use of VEGF for bone regeneration in a clinical setting.

Effects of vascular endothelial growth factor and insulin growth factor‑1 on proliferation, migration, osteogenesis and vascularization of human carious dental pulp stem cells.

The present study aimed to investigate the effects of vascular endothelial growth factor (VEGF) and insulin‑like growth factor‑1 (IGF‑1) on the proliferation, migration and differentiation of human carious dental pulp stem cells (hCDPSCs), and to elucidate the underlying mechanism(s). Cell counting kit‑8 assay was used to detect the effect of different concentrations of IGF‑1 and VEGF on the proliferation of hCDPSCs. Transwell assay was used to detect the migratory ability of the hCDPSCs. Alizarin red and alkaline phosphatase (ALP) staining were used to detect the osteogenic ability of hCDPSCs, whereas the angiogenic ability of the hCDPSCs was tested by tube formation assay. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were used to detect the expression levels of associated genes and proteins. IGF‑1 (100ng/ml) or VEGF (25ng/ml) alone were revealed to be able to promote proliferation and migration of hCDPSCs; however, the combined use of IGF‑1 and VEGF enhanced this effect when compared with the use of either agent in isolation. Alizarin red and ALP staining revealed that the use of either VEGF or IGF‑1 alone did not result in any significant effects, whereas their use in combination promoted the osteogenic differentiation of hCDPSCs. In addition, the RT‑qPCR and western blotting analyses revealed that the expression levels of Runt‑related transcription factor 2 (RUNX2), bone sialoprotein (BSP) and ALP were increased upon combined treatment of the cells with VEGF and IGF‑1. The expression levels of VEGF and plateletderived growth factor (PDGF) in hCDPSCs were enhanced upon treatment with either VEGF or IGF‑1 in isolation, with greater effects observed when VEGF and IGF‑1 were added in combination, indicating that VEGF and IGF‑1 may exert a synergistic role in these events. Further experiments revealed that the combination of VEGF and IGF‑1 led to an activation of the AKT signaling pathway. The proliferation and angiogenesis of hCDPSCs were also shown to be more effective compared with treatment with either VEGF or IGF‑1 in isolation. Taken together, the present study has demonstrated that the combined use of VEGF and IGF‑1 leads to an increase in the proliferation, migration, osteogenesis and angiogenesis of hCDPSCs and, furthermore, these signaling molecules may mediate their effects via activation of the AKT signaling pathway.

Expression of VEGF in breast lesions: an immunohistochemical study

Background: Breast cancer is the most frequent cancer in India. During the last few years, several investigators have focused on tumor angiogenesis as a critical step in cancer development and progression. Among these, vascular endothelial growth factor (VEGF) is emerging as a prognostic marker in patients with several type of cancer including breast cancer. The aim of the study was to analyse the expression of VEGF in human breast cancer as compared to normal breast tissue and benign breast lesions by immunohistochemistry. Also, to assess the usefulness of VEGF as a predictor of aggressiveness of breast lesions.Methods: Formalin fixed paraffin embedded sections of 10 cases of normal breast tissue, 20 cases of benign breast lesions and 20 cases of malignant breast lesions were taken up for the study and subjected to immunohistochemistry using VEGF.Results: The intensity of VEGF immunostaining in normal breast, benign and malignant breast lesions was evaluated and scoring was graded as 0, 1+, 2+, 3+ and 4+. Statistical analysis was performed with Chi-Square test and significant differences were noted between these 3 groups (p value &lt;0.05).Conclusions:VEGF expression correlated well with the grade and stage of tumor indicating that VEGF positive tumors are biologically aggressive and are associated with poor prognosis but little is known about the implication of genetic alterations of VEGF in benign breast lesions.

Uveal Melanoma Cell Under Oxidative Stress - Influence of VEGF and VEGF-Inhibitors

The role of oxidative stress in cancer is complex. While the pathological alterations induced by oxidative stress may be involved in the induction of tumours, in the late stages of tumour development, it can facilitate the loss of tumour cells and might even prevent metastasis. Tumour cells show metabolic alterations, often inducing an increased production of reactive oxygen species, which makes these cells particularly vulnerable to additional oxidative stress. This is an important mode of action in the use of many chemotherapeutics and in the application of ionizing radiation. Uveal melanoma is the most frequent primary tumour in the adult eye. For metastasis of this tumour, which affects about 50 % of the patients, no appropriate treatment is currently available. However, the primary tumour can efficiently be treated with ionizing radiation. A frequent side effect of this treatment is radiation retinopathy, which is treated with vascular endothelial growth factor (VEGF) antagonists. A therapy of the primary tumour with VEGF antagonists is under discussion. So far, little data is available on this subject, however, a paradoxical worsening of the situation has been found in a mouse model of uveal melanoma treated with bevacizumab. We have investigated the effect of VEGF and of the VEGF-antagonist bevacizumab on the survival of five different melanoma cell lines under oxidative stress treatment with hydrogen peroxide. In addition, we investigated the expression of relevant proteins and the effect of bevacizumab on the proliferation of the cells as well as its effect on the angiogenic behaviour of endothelial cells, co-cultured with uveal melanoma cells. Our study showed that not only VEGF but also, paradoxically, the VEGF-antagonist bevacizumab is able to protect uveal melanoma cells from oxidative stress-induced cell death. Bevacizumab did not influence the proliferation of the cells and showed only limited effectiveness to reduce angiogenic structures. Considering that oxidative stress is the mode of action for ionizing radiation to induce cell death, a protective effect of bevacizumab on uveal melanoma cells against oxidative stress is worrisome and argues against the use of VEGF in uveal melanoma.

Application of VEGF Gene Therapy in Two Basic Fields of Plastic- Reparative Surgery: Tissue Reconstruction with Flaps and Peripheral Nerve Surgery

Experimental works in the field of reconstructive plastic surgery have been especially focused in restorative procedures based on flaps and peripheral nerve regeneration. Those involving the use of VEGF gene therapy showed generated particular interest but also many significant conclusions in both fields of reconstructive surgery which are currently introducing in the operating room. Interestingly, composite tissue allotransplantation methods joined the possibility to perform anatomical and functional reconstructions, since skin, muscle or bones can be transferred together, but also the concomitant nerves, which will be responsible to produce the movements of these transplanted tissues like in facial transplantation or limb transplantation. During reconstructive surgeries involving flaps, partial or complete ischemia of tissues can be a common complication, especially after free tissue transfer. For this reason, there is always a reasonable risk of flap necrosis that can lead to the loss of the reconstructive procedure due to venous or/and arterial insufficiency. On the other hand, after nerve damage, axons distal to the nerve crush begin to degenerate. As a consequence, the functional connections between motor axons and muscles are finally damaged leading to progressive muscle atrophy. When nerve continuity is repaired, the proximal stumps of injured axons are in condition to sprout within the distal nerve stumps. Experimental studies demonstrated the utility and efficiency of growth factors in stimulating neoangiogenesis in order to improve flap survival as well as in the promotion of axonal sprouting which is an important point for nerve regeneration. Among the ones, the Vascular Endothelial Growth Factor (VEGF) has shown to be an efficient therapeutic agent in both fields. Gene therapy based on adeno-associated viruses, liposomes or nanoparticles is the accepted method to develop the new angiogenesis and nerve promotion as these carriers are able to efficiently deliver therapeutic genes to flaps and nerves. Nevertheless, there are still many obstacles to be solved like the therapeutic maintenance of VEGF production along the period of time necessary to perform the desired effects, but also the use of VEGF as a preventive factor to avoid flap failure in reconstructive procedures. This reviews describes the advances in regenerative medicine in flap and nerve surgery using VEGF gene therapy and related patents. Keywords: Adenovirus, flaps, gene therapy, liposomes, nanoparticles, nerve regeneration, peripheral nerve, reconstructive surgery, VEGF.

Orai1 and Transient Receptor Potential Channels as Novel Molecular Targets to Impair Tumor Neovascularization in Renal Cell Carcinoma and other Malignancies

The term "angiogenic switch" describes one of the earlier events of tumorigenesis, that occurs when the balance between pro-and anti-angiogenic factors shifts towards a pro-angiogenic outcome. This leads to the transition from a microscopic indolent lesion to a macroscopic and vascularised primary tumor, that may eventually metastasize and spread to distant sites. The molecular mechanisms underlying such a critical step in the carcinogenetic process have been extensively investigated. Both local endothelial cells (ECs) and endothelial progenitor cells (EPCs), recruited from bone marrow, have been implicated in the angiogenic switch, which is ultimately triggered by a plethora of growth factors released by cancer cells, pivotal among which is vascular endothelial growth factor (VEGF); indeed, VEGF both activates ECs nearby the growing tumor, and leads to EPC mobilization into the circulation. In kidney, in particular, the frequent mutation of the Von Hippel Lindau tumor suppressor gene leads to an overproduction of pro-angiogenic factors which makes this neoplasm quite sensitive to antiangiogenic drugs. However, it is now evident that the use of VEGF(Rs) inhibitors in everyday clinical practice is not as effective as observed in murine models. The investigation of alternative signaling pathways involved in the angiogenic switch is, therefore, imperative in order to induce tumor regression whereby preventing harmful drawback consequences. Ca(2+) entry across the plasma membrane has long been known to stimulate mature ECs to undergo angiogenesis. Recent work from several groups worldwide has then outlined that members of the Transient Receptor Potential (TRP) super-family of cationic channels and Orai1 provide the pathway for such proangiogenic Ca(2+) signal. In addition, Canonical TRP 1 (TRPC1) and Orai1 channels control proliferation and tubulogenesis in both normal EPCs and EPCs isolated from peripheral blood of tumor patients. As a consequence, TRP channels and Orai1 might serve as novel molecular targets to develop alternative and more effective strategies of angiogenesis inhibition.

Effects of Vascular Endothelial Growth Factor on Survival of Surgical Flaps: A Review of Experimental Studies

Partial or complete necrosis of skin flaps remains a significant problem in plastic and reconstructive surgery. Growth factors have shown promise in improving flap survival through increased angiogenesis and blood supply to the flap. Vascular endothelial growth factor (VEGF) is the most widely investigated and successful one. But the mechanisms of the effects are still not very clear. In the course of a series of experiments, we indicated that tissue survival of surgical flaps could be improved by both preoperative (sustained phase effect) and intraoperative (acute phase effect) application of VEGF. We reviewed both experimental and clinical investigations on the use of VEGF with surgical flaps to summarize the evidence of both phases of VEGF activity in promotion of flaps survival in detail. With the combinations of acute and sustained phases of effects, VEGF protein and gene, VEGF morphologic actions, and VEGF histochemical modulations suggest a pattern of VEGF activity that can be superimposed on classic descriptive mechanisms of tissue survival of flaps.

Therapeutic Approaches to the Regulation of Wound Angiogenesis

Re-establishment of a functional vascular network is a critical component of successful wound repair. One of the most potent pro-angiogenic agents is vascular endothelial growth factor (VEGF), which, from a basic science and pre-clinical perspective, seems ideal for the therapeutic stimulation of blood vessel growth in non-healing wounds. Current strategies to improve the dysfunctional angiogenesis that occurs in non-healing wounds are inadequate with regard to the nature and magnitude of the clinical problem. However, VEGF therapy has so far been unsuccessful in promoting healing in the clinic. More effective means of delivery to the wound, which take into account the biochemical and spatio-temporal aspects of angiogenesis, may be necessary to realize VEGF's therapeutic potential. Reviewed approaches for the regulation of wound angiogenesis include: targeting regulators of intracellular VEGF signaling, making use of collagen-binding VEGF fusion proteins for increased retention in the wound, and implantation of heterogeneous scaffold systems for spatial control of angiogenesis with simultaneous use of VEGF and its inhibitor. To maximize efficacy of therapeutic VEGF, it may be necessary to also target its intracellular inhibitory mechanisms. Immobilizing VEGF to the wound matrix may increase its bioavailability and therapeutic efficacy. Gaining spatial control of angiogenesis opens up possibilities for advanced directed therapy. The reviewed studies present innovative approaches to in vivo directed modulation of angiogenesis utilizing VEGF biology which can, if taken further and validated in human subjects, have significant impact on clinical wound care in the future.

Cellular and molecular mechanisms involved in the neuroprotective effects of VEGF on motoneurons

Vascular endothelial growth factor (VEGF), originally described as a factor with a regulatory role in vascular growth and development, it is also known for its direct effects on neuronal cells. The discovery in the past decade that transgenic mice expressing reduced levels of VEGF developed late-onset motoneuron pathology, reminiscent of amyotrophic lateral sclerosis (ALS), opened a new field of research on this disease. VEGF has been shown to protect motoneurons from excitotoxic death, which is a relevant mechanism involved in motoneuron degeneration in ALS. Thus, VEGF delays motoneuron degeneration and increases survival in animal models of ALS. VEGF exerts its anti-excitotoxic effects on motoneurons through molecular mechanisms involving the VEGF receptor-2 resulting in the activation of the PI3-K/Akt signaling pathway, upregulation of GluR2 subunit of AMPA receptors, inhibition of p38MAPK, and induction of the anti-apoptotic molecule Bcl-2. In addition, VEGF acts on astrocytes to reduce astroglial activation and to induce the release of growth factors. The potential use of VEGF as a therapeutic tool in ALS is counteracted by its vascular effects and by its short effective time frame. More studies are needed to assess the optimal isoform, route of administration, and time frame for using VEGF in the treatment of ALS.