The relationship between vascular endothelial growth factor (VEGF) in the serum and drained dialysate with the quality of peritoneal dialysis and peritoneal membrane transport rates

Vascular endothelial growth factor (VEGF), a powerful angiogenetic agent crucial for microvascular hyperpermeability and neoangiogenesis in the peritoneum, is associated with increased solute transport rates in chronic peritoneal dialysis (PD) patients. We investigated the correlation between serum and drained dialysate (dd) concentrations of VEGF and the transport characteristics of peritoneal membrane and dialysis quality in 20 patients with end-stage renal failure at the beginning and after six months of PD. The serum VEGF (sVEGF) concentration rose significantly (149.33?}116.71 pg/ mL vs 239.36?}102.23 pg/mL; p=0.012) and ddVEGF concentration increased slightly (38.44?}50.47 pg/mL vs 43.55?}51.10 pg/mL) during the first 6 months of PD. At the beginning of chronic PD, ddVEGF concentrations correlated inversely with the peritoneal equilibrium test (PET) glucose (R=-0.565; p=0.009) and creatinine (R=-0.506; p=0.023) and residual renal function (RRF) (R=-0.691; p=0.001); sVEGF concentrations inversely correlated with PET creatinine (R=-0.457; p=0.043) and residual diuresis (RD) (R=-0.691; p=0.001). After 6 months of treatment, ddVEGF concentrations correlated directly with PETcreatinine (R=0.450; p=0.047), and inversely with RRF (R=-0.552; p=0.012) and residual renal weekly Kt/V (R=-0.488; p=0.029). The sVEGF concentration inversely correlated with RD (R=-0.589; p=0.006). High ddVEGF at the beginning of PD is predictive of adverse alterations of the peritoneal membrane, i.e. increased transport rate of glucose and creatinine. ddVEGF values may help to identify patients who will preserve adequate transport characteristics of the peritoneal membrane and maintain successful long-term PD.

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Vascular Endothelial Growth Factor Is Essential for Hyperglycemia-Induced Structural and Functional Alterations of the Peritoneal Membrane

Journal of the American Society of Nephrology ◽

10.1681/asn.v1281734 ◽

2001 ◽

Vol 12 (8) ◽

pp. 1734-1741 ◽

Cited By ~ 4

Author(s):

AN S. DE VRIESE ◽

RONALD G. TILTON ◽

CLIFFORD C. STEPHAN ◽

NORBERT H. LAMEIRE

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

High Glucose ◽

Microvascular Dysfunction ◽

Vascular Endothelial ◽

Peritoneal Membrane ◽

Long Term Treatment ◽

Glucose Exposure ◽

Endothelial Growth Factor

Abstract. Long-term peritoneal dialysis is associated with the development of functional and structural alterations of the peritoneal membrane. Long-term exposure to the high glucose concentrations in conventional peritoneal dialysate has been implicated in the pathogenesis of peritoneal hyperpermeability and neoangiogenesis. Vascular endothelial growth factor (VEGF) is an endothelial-specific growth factor that potently stimulates microvascular permeability and proliferation. High glucose exposure upregulates VEGF expression in various cell types and tissues. This study investigated whether VEGF plays a pathogenetic role in hyperglycemia-induced microvascular dysfunction in the peritoneal membrane. The peritoneal microcirculation of streptozotocin-induced diabetic rats and age-matched controls was studiedin vivowith a combination of functional and morphologic techniques. The diabetic microcirculation was characterized by an elevated transport of small solutes, indicating the presence of an increased effective vascular surface area. The leakage of FITC-albumin was more rapid in diabetic vessels, suggesting hyperpermeability for macromolecules. Structurally, an increased vascular density with focal areas of irregular capillary budding was found in the diabetic peritoneum. The hyperglycemia-induced structural and functional microvascular alterations were prevented by long-term treatment with neutralizing anti-VEGF monoclonal antibodies, whereas treatment with isotype-matched control antibodies had no effect. VEGF blockade did not influence microvascular density or macromolecular leakage in control rats, demonstrating specificity for the hyperglycemia-induced alterations. The present results thus support an causative link among high glucose exposure, upregulation of VEGF, and peritoneal microvascular dysfunction.

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Vascular endothelial growth factor-mediated peritoneal neoangiogenesis in peritoneal dialysis

Peritoneal Dialysis International ◽

10.1177/08968608211004683 ◽

2021 ◽

pp. 089686082110046

Author(s):

Yingfeng Shi ◽

Yan Hu ◽

Binbin Cui ◽

Shougang Zhuang ◽

Na Liu

Keyword(s):

Vascular Endothelial Growth Factor ◽

Peritoneal Dialysis ◽

Growth Factor ◽

Vascular Endothelial Cells ◽

Renal Diseases ◽

Vascular Endothelial ◽

Ultrafiltration Failure ◽

Tumour Growth Factor ◽

End Stage ◽

Endothelial Growth Factor

Peritoneal dialysis (PD) is an important renal replacement therapy for patients with end-stage renal diseases, which is limited by peritoneal neoangiogenesis leading to ultrafiltration failure (UFF). Vascular endothelial growth factor (VEGF) and its receptors are key angiogenic factors involved in almost every step of peritoneal neoangiogenesis. Impaired mesothelial cells are the major sources of VEGF in the peritoneum. The expression of VEGF will be up-regulated in specific pathological conditions in PD patients, such as with non-biocompatible peritoneal dialysate, uremia and inflammation, and so on. Other working cells (i.e. vascular endothelial cells, macrophages and adipocytes) can also stimulate the secretion of VEGF. Meanwhile, hypoxia and activation of complement system further aggravate peritoneal injury and contribute to neoangiogenesis. There are several signalling pathways participating in VEGF-mediated peritoneal neoangiogenesis including tumour growth factor-β, Wnt/β-catenin, Notch and interleukin-6/signal transducer and activator of transcription 3. Moreover, VEGF is highly expressed in dialysate effluent of long-term PD patients and is associated with peritoneal transport function, which supports its role in the alteration of peritoneal structure and function. In this review, we systematically summarize the angiogenic effect of VEGF and evaluate it as a potential target for the prevention of peritoneal neoangiogenesis and UFF. Preservation of the peritoneal membrane using targeted therapy of VEGF-mediated peritoneal neoangiogenesis may increase the longevity of the PD modality for those who require life-long dialysis.

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By Reducing Production of Vascular Endothelial Growth Factor Octreotide Improves the Peritoneal Vascular Alterations Induced by Hypertonic Peritoneal Dialysis Solution

Peritoneal Dialysis International ◽

10.1177/089686080202200302 ◽

2002 ◽

Vol 22 (3) ◽

pp. 301-306 ◽

Cited By ~ 12

Author(s):

Ali Ihsan Günal ◽

Hüseyin Celiker ◽

Nusret Akpolat ◽

Bilal Üstündag ◽

Soner Duman ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Peritoneal Dialysis ◽

Growth Factor ◽

Control Group ◽

Hypertonic Solution ◽

Vascular Endothelial ◽

Peritoneal Membrane ◽

Plasma Urea ◽

Endothelial Growth Factor ◽

Peritoneal Function

Objective Chronic peritoneal dialysis (PD) may eventually result in vascular alterations of varying degree, which lead to progressive reduction in dialytic efficacy. Although the pathogenesis has not been elucidated yet, vascular endothelial growth factor (VEGF) has been proposed to play a central role in the process leading to vascular alterations. Design Rats were allocated to three groups: no treatment, intraperitoneal introduction of hypertonic PD solution alone, and intraperitoneal introduction of hypertonic PD solution plus octreotide. After 4 weeks, a 1-hour peritoneal equilibration test (PET) was performed. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D1/D0 glucose), ultrafiltration volume (UF), and levels of dialysate protein and VEGF were determined. Peritoneal membrane histology was evaluated by light microscopy. Results Compared with the control group, rats treated with hypertonic PD solution showed dramatically deranged peritoneal function tests (UF: 5.8 ± 0.9 mL vs 1.3 ± 0.6 mL; D/P urea: 0.49 ± 0.1 vs 0.74 ± 0.04; D1/D0 glucose: 0.55 ± 0.05 vs 0.34 ± 0.06) and morphology (thickness: 4.6 ± 0.4 μ vs 62 ± 12 μ; neovascularisation: 0.1 ± 0.3 vessels per field vs 2.2 ± 0.3 vessels per field). Similarly, a higher level of VEGF was found in the rats treated with hypertonic PD solution. In rats treated with hypertonic solution plus octreotide, peritoneal thickness was not completely reduced (25 ± 5 μ), but peritoneal functions were protected (UF: 4.0 ± 0.5 mL; D/P urea: 0.58 ± 0.02; D1/D0 glucose: 0.51 ± 0.02). Moreover, VEGF level and neoangiogenesis were significantly less in the octreotide group than in the group treated with hypertonic dextrose alone. Conclusion Our data document that, by increasing the production of VEGF, a high glucose concentration can cause vascular alterations within the peritoneal membrane. Octreotide can protect against the vascular alterations and preserve peritoneal function by inhibiting overexpression of VEGF and regulating the inflammatory response in the peritoneum.

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Long-Term Stability of Anti-Vascular Endothelial Growth Factor (a-VEGF) Biologics Under Physiologically Relevant Conditions and Its Impact on the Development of Long-Acting Delivery Systems

Journal of Pharmaceutical Sciences ◽

10.1016/j.xphs.2020.09.043 ◽

2020 ◽

Author(s):

Debby P. Chang ◽

Shalini Burra ◽

Eric S. Day ◽

Joyce Chan ◽

Laetitia Comps-Agrar ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Delivery Systems ◽

Vascular Endothelial ◽

Term Stability ◽

Long Term Stability ◽

Long Acting ◽

Endothelial Growth Factor

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Long-term Anti–Vascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration: The LATAR Study

Ophthalmology Retina ◽

10.1016/j.oret.2020.09.019 ◽

2020 ◽

Author(s):

Kimberly Spooner ◽

Samantha Fraser-Bell ◽

Thomas Hong ◽

Long Phan ◽

James G. Wong ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Vascular Endothelial ◽

Age Related ◽

Endothelial Growth Factor ◽

Growth Factor Treatment

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Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation

Cells ◽

10.3390/cells11020210 ◽

2022 ◽

Vol 11 (2) ◽

pp. 210

Author(s):

Silvia Graziani ◽

Luca Scorrano ◽

Giovanna Pontarin

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Protein Synthesis ◽

Growth Factor ◽

Drug Withdrawal ◽

Growth Factor Receptor ◽

Vascular Endothelial ◽

P53 Expression ◽

Endothelial Growth Factor

Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how transient exposure to Dox leads to long-term downregulation of Endothelial Vascular Endothelial Growth Factor Receptor type2 (VEGFR2), essential for endothelial cells function. Using an in vitro model devised to study the long-lasting effects of brief endothelial cells exposure to Dox, we show that Dox leads to sustained protein synthesis inhibition and VEGFR2 downregulation. Transient Dox treatment led to the development of long-term senescence associated with a reduction in VEGFR2 levels that persisted days after drug withdrawal. By analyzing VEGFR2 turnover, we ruled out that its downregulation was depended on Dox-induced autophagy. Conversely, Dox induced p53 expression, reduced mTOR-dependent translation, and inhibited global protein synthesis. Our data contribute to a mechanistic basis to the permanent damage caused to endothelial cells by short-term Dox treatment.

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