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• W2012536700 abstract "vascular endothelial growth factor VEGF receptor soluble VEGFR To the Editor: During cutaneous wound healing, the development of granulation tissue requires the formation of new capillaries, and the absence of this tissue is a typical feature of chronic non-healing wounds (Luetolf et al., 1993Luetolf O. Bull R.H. Bates D.O. Mortimer P.S. Capillary underperfusion in chronic venous insufficienc: A cause for leg ulceration?.Br J Dermatol. 1993; 128: 249-254Crossref PubMed Scopus (37) Google Scholar;Bollinger et al., 1997Bollinger A. Leu A.J. Hoffmann U. Franzeck U.K. Microvascular changes in venous disease: An update.Angiology. 1997; 48: 27-32Crossref PubMed Scopus (74) Google Scholar). Local mechanisms leading to impaired angiogenesis in chronic non-healing wounds are poorly understood. Vascular endothelial growth factor (VEGF)-A is a pivotal molecule in driving the angiogenic response in wound repair (Brown et al., 1992Brown L.F. Yeo K.T. Berse B. Yeo T.K. Senger D.R. Dvorak H.F. Van De Water L. Expression of VEGF by epidermal keratinocytes during wound healing.J Exp Med. 1992; 176: 1375-1379Crossref PubMed Scopus (778) Google Scholar;Frank et al., 1995Frank S. Hübner G. Breier G. Longaker M.T. Greenhalgh D.G. Werner S. Regulation of VEGF expression in cultured keratinocytes.J Biol Chem. 1995; 270: 12607-12613https://doi.org/10.1074/jbc.270.21.12607Crossref PubMed Scopus (677) Google Scholar;Nissen et al., 1998Nissen N.N. Polverini P.J. Koch A.E. Volin M.V. Gamelli R.L. DiPietro L.A. VEGF mediates angiogenic activity during the proliferative phase of wound healing.Am J Pathol. 1998; 152: 1445-1452PubMed Google Scholar;Kishimoto et al., 2000Kishimoto J. Ehama R. Ge Y. Kobayashi T. Nishiyama T. Detmar M. Burgeson R.E. In vivo detection of VEGF promoter activity in transgenic mouse skin.Am J Pathol. 2000; 157: 103-110Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar;Kuo et al., 2001Kuo C.J. Farnebo F. Yu E.Y. et al.Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer.Proc Natl Acad Sci. 2001; 98: 4505-4610Google Scholar). So far, soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), a splice variant of the membrane-bound VEGFR-1, is considered the only naturally occurring specific inibitor for VEGF-A. In vitro analysis demonstrated that sVEGFR-1 is a strong and specific inhibitor of VEGF-A-mediated actions and in vivo studies proved that the recombinant secreted form of the extracellular region of VEGFR-1 is a potent inhibitor of angiogenesis (Kendall and Thomas, 1993Kendall R.L. Thomas K.A. Inhibition of VEGF activity by an endogenously encoded soluble receptor.Proc Natl Acad Sci. 1993; 90: 10705-10709Crossref PubMed Scopus (1189) Google Scholar;Aiello et al., 1995Aiello L.P. Pierce E.A. Foley E.D. et al.Suppression of retinal neovascularization in vivo by inhibition of VEGF using soluble VEGF-receptor chimeric proteins.Proc Natl Acad Sci. 1995; 92: 10457-10461Crossref PubMed Scopus (1163) Google Scholar;Miotla et al., 2000Miotla J. Maciewicz R. Kendrew J. Feldmann M. Paleolog E. Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis.Lab Invest. 2000; 80: 1195-1205Crossref PubMed Scopus (157) Google Scholar;Mori et al., 2000Mori A. Arii S. Furutani M. et al.Soluble Flt-1 gene therapy for peritoneal metastases using HVJ-cationic liposomes.Gene Ther. 2000; 7: 1027-1033https://doi.org/10.1038/sj.gt.3301202Crossref PubMed Scopus (62) Google Scholar). Potentially, sVEGFR-1 functions as an inert decoy receptor by binding VEGF-A and thereby regulating the availability of VEGF-related ligands for activation of VEGFR-2 (Flk-1/KDR), the VEGF receptor principally involved in VEGF signalling (Kendall and Thomas, 1993Kendall R.L. Thomas K.A. Inhibition of VEGF activity by an endogenously encoded soluble receptor.Proc Natl Acad Sci. 1993; 90: 10705-10709Crossref PubMed Scopus (1189) Google Scholar;Barleon et al., 1997Barleon B. Siemeister G. Martiny-Baron G. Weindel K. Herzog C. Marme D. VEGF up-regulates its receptor fms-like tyrosine kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial cells.Cancer Res. 1997; 57: 5421-5425PubMed Google Scholar;Hiratsuka et al., 1998Hiratsuka S. Minowa O. Kuno J. Noda T. Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice.Proc Natl Acad Sci. 1998; 95: 9349-9354https://doi.org/10.1073/pnas.95.16.9349Crossref PubMed Scopus (887) Google Scholar). Beside VEGF-A, VEGFR-1 binds the VEGF-related proteins placenta growth factor (PIGF) and VEGF-B, but with much lower affinity (Kendall and Thomas, 1993Kendall R.L. Thomas K.A. Inhibition of VEGF activity by an endogenously encoded soluble receptor.Proc Natl Acad Sci. 1993; 90: 10705-10709Crossref PubMed Scopus (1189) Google Scholar;Hornig et al., 2000Hornig C. Barleon B. Ahmad S. Vuerola P. Ahmed A. Weich H.A. Release and complexed formation of soluble VEGFR-1 form endothelial cells and biological fluids.Lab Invest. 2000; 80: 443-454Crossref PubMed Scopus (191) Google Scholar;Shibuya, 2001Shibuya M. Structure and dual function of VEGF receptor-1 (Flt-1).Int J Biochem Cell Biol. 2001; 33: 409-420https://doi.org/10.1016/S1357-2725(01)00026-7Crossref PubMed Scopus (215) Google Scholar). Although the precise function of PIGF and VEGF-B during cutaneous wound repair is presently unknown, recent data indicate that membrane-bound VEGFR-1 might be a critical signalling receptor for PIGF during cutaneous tissue repair (Failla et al., 2000Failla C.M. Odorisio T. Cianfarani F. Schietroma C. Puddu P. Zambruno G. PIGF is induced in human keratinocytes during wound healing.J Invest Dermatol. 2000; 115: 388-395https://doi.org/10.1046/j.1523-1747.2000.00085.xCrossref PubMed Scopus (94) Google Scholar;Carmeliet et al., 2001Carmeliet P. Moons L. Luttun A. et al.Synergism between VEGF and PIGF contributes to angiogenesis and plasma extravasation in pathological conditions.Nature Med. 2001; 7: 575-583Crossref PubMed Scopus (1386) Google Scholar). Expression of sVEGFR-1 has been described in a variety of primary human endothelial cells, in various cancer tissues and different biological fluids (Kendall and Thomas, 1993Kendall R.L. Thomas K.A. Inhibition of VEGF activity by an endogenously encoded soluble receptor.Proc Natl Acad Sci. 1993; 90: 10705-10709Crossref PubMed Scopus (1189) Google Scholar;Barleon et al., 1997Barleon B. Siemeister G. Martiny-Baron G. Weindel K. Herzog C. Marme D. VEGF up-regulates its receptor fms-like tyrosine kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial cells.Cancer Res. 1997; 57: 5421-5425PubMed Google Scholar;Banks et al., 1998Banks R.E. Forbes M.A. Searles J. et al.Evidence for the existence of a novel pregnancy-associated soluble variant of the VEGF receptor, Flt-1.Hum Reprod Embryol. 1998; 4: 377-386Crossref PubMed Scopus (104) Google Scholar;Hornig et al., 1999Hornig C. Behn T. Bartsch W. Yayon A. Weich H.A. Detection and quantification of complexed and free soluble human VEGF receptor-1 by ELISA.J Immunol Methods. 1999; 226: 169-177https://doi.org/10.1016/S0022-1759(99)00065-4Crossref PubMed Scopus (47) Google Scholar;Hornig et al., 2000Hornig C. Barleon B. Ahmad S. Vuerola P. Ahmed A. Weich H.A. Release and complexed formation of soluble VEGFR-1 form endothelial cells and biological fluids.Lab Invest. 2000; 80: 443-454Crossref PubMed Scopus (191) Google Scholar;Vuorela et al., 2000Vuorela P. Helske S. Hornig C. Alitalo K. Weich H.A. Halmesmäki E. Amniotic fluid-soluble VEGF receptor-1 in preeclapsia.Am Coll Obstet Gynecol. 2000; 95: 353-357Crossref PubMed Scopus (117) Google Scholar;Barleon et al., 2001Barleon B. Reusch P. Totzke F. Herzog C. Keck C. Martiny-Baron G. Marme D. Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma form healthy donors.Angiogenesis. 2001; 4: 143-154Crossref PubMed Scopus (96) Google Scholar;Tor et al., 2002Tor M. Bando H. Ogawa T. Muta M. Hornig C. Weich H.A. Significance of VEGF/soluble VEGF receptor-1 relationship in breast cancer.Int J Cancer. 2002; 98: 14-18https://doi.org/10.1002/ijc.10121.absCrossref PubMed Google Scholar). The significance of naturally occurring sVEGFR-1 is unclear at this time. In this study we investigated the hypothesis whether sVEGFR-1 plays a role during cutaneous wound repair and we evaluated the expression of sVEGFR-1 in normal healing and chronic non-healing cutaneous wounds. To assess sVEGFR-1 secretion, sVEGFR-1 protein was quantified by ELISA in wound fluid obtained from patients of normal healing cutaneous acute wounds after patients provided written, informed consent (patients n=11, excision wounds of the lower leg awaiting wound closure by secondary intention, postoperative days 3 or 4, mean age of patients 65±16 y) and non-healing chronic wounds of patients presenting with chronic venous insufficiency (patients n=16, duration of ulcer >6 months, mean size 84±49 cm2, mean age of patients 71±11 y, ulcers showed no clinical sign of infection and poor granulation tissue formation). In wound fluid of normal healing wounds sVEGFR-1 levels averaged at 2.2±2.0 ng per mL. In contrast, mean sVEGFR-1 concentration in wound fluid obtained from chronic non-healing wounds was 9.34±3.2 ng per mL (p<0.0001) (Figure 1a). sVEGFR-1 levels in serum from patients with healing and non-healing wounds were below 1 ng per mL, indicating that sVEGFR-1 protein was synthesized and secreted locally at the wound site. Additionally, the presence of sVEGFR-1 in wound fluid was verified by western blot analysis (Figure 1b). The sVEGFR-1 protein present in wound fluid had a molecular weight of approximately 110 kd, comparable to native sVEGFR-1 isolated from HUVEC or placenta cell-conditioned media (Figure 1b) (Kendall and Thomas, 1993Kendall R.L. Thomas K.A. Inhibition of VEGF activity by an endogenously encoded soluble receptor.Proc Natl Acad Sci. 1993; 90: 10705-10709Crossref PubMed Scopus (1189) Google Scholar;Hornig et al., 1999Hornig C. Behn T. Bartsch W. Yayon A. Weich H.A. Detection and quantification of complexed and free soluble human VEGF receptor-1 by ELISA.J Immunol Methods. 1999; 226: 169-177https://doi.org/10.1016/S0022-1759(99)00065-4Crossref PubMed Scopus (47) Google Scholar). Further, expression of sVEGFR-1 and VEGFR-1 in chronic wound tissue was demonstrated by RT-PCR analysis and Southern blot analysis of the RT-PCR products (Figure 1c). Additionally, the specificity of the RT-PCR products was verified by DNA sequencing. To assess the heterogeneity of sVEGFR-1 concentrations, particular in chronic wound fluid samples, we investigated the kinetics of sVEGFR-1 release at different stages during the healing process. Progression in wound healing was evaluated by assessing granulation tissue formation and re-epithelialization by wound tracings at indicated time points. sVEGFR-1 levels quantified in wound fluid collected from normal healing wounds were low at initial postoperative days, similar to serum levels, increased during granulation tissue formation up to a maximum and decreased with wound closure (Figure 2a). During a 2-mo follow-up in our clinic some of the chronic wounds transformed from a non-healing in a healing state, characterized by granulation tissue formation and finally wound closure. In these patients induction of granulation tissue formation and wound closure was associated with a decrease in sVEGFR-1 concentrations (Figure 2b, wounds #4–6); the positive correlation between healing progression and sVEGFR-1 decline was statistically significant (r=0.92, p<0.0005). In contrast, sVEGFR-1 levels in chronic wounds which did not develop granulation tissue and did not diminish in wound size over a period of 2 mo remained high (Figure 2b, wounds #7–9). For all wounds therapy followed the principals of moist wound therapy combined with compression therapy in venous ulcers. Interestingly, the kinetics of sVEGFR-1 secretion in normal healing wounds resembles those described for VEGF-A/PIGF expression during normal wound repair, indicating a temporal correlation of sVEGFR-1 and VEGF ligand expression during wound angiogenesis (Nissen et al., 1998Nissen N.N. Polverini P.J. Koch A.E. Volin M.V. Gamelli R.L. DiPietro L.A. VEGF mediates angiogenic activity during the proliferative phase of wound healing.Am J Pathol. 1998; 152: 1445-1452PubMed Google Scholar;Failla et al., 2000Failla C.M. Odorisio T. Cianfarani F. Schietroma C. Puddu P. Zambruno G. PIGF is induced in human keratinocytes during wound healing.J Invest Dermatol. 2000; 115: 388-395https://doi.org/10.1046/j.1523-1747.2000.00085.xCrossref PubMed Scopus (94) Google Scholar;Carmeliet et al., 2001Carmeliet P. Moons L. Luttun A. et al.Synergism between VEGF and PIGF contributes to angiogenesis and plasma extravasation in pathological conditions.Nature Med. 2001; 7: 575-583Crossref PubMed Scopus (1386) Google Scholar). This observation supports the idea that during physiological angiogenesis sVEGFR-1 may control a local overshooting response of the increasing VEGF-related ligands. In contrast, induction of sVEGFR-1 expression to non-physiological levels, as measured in chronic non-healing wounds, indicate a disturbance of the VEGF ligand/sVEGFR-1 balance; potentially, this dysregulation may attenuate vessel growth during granulation tissue formation and hence impair wound closure. To investigate whether wound fluid contains mediators capable of inducing VEGFR-1 and sVEGFR-1 mRNA expression, we analyzed VEGFR-1 and sVEGFR-1 mRNA expression in HUVE cells following exposure to wound fluid. Densitometric analysis of the corresponding Northern blot analysis demonstrated that wound fluid obtained from chronic non-healing wounds was significantly stronger in inducing sVEGFR-1 mRNA expression in comparision to wound fluid obtained from healing wounds (data not shown). This data suggests that inducing sVEGFR-1 expression to non-physiological levels could not only be regarded as a cause, but also as a consequence of chronic ulceration and opens new prospective in understanding which factor in wound fluid is responsible for such an induction. In summary, our report reveales the expression of sVEGFR-1 during cutaneous wound healing suggesting a function of sVEGFR-1 during tissue repair. Whether increased sVEGFR-1 levels in non-healing wounds interfere with the activities of VEGF-related ligands and potentially reduce angiogenesis remains to be investigated in further studies. Our results, however, lead to the intriguing hypothesis as to whether the sVEGFR-1 level detected in wound fluid can be of prognostic value for differentiating an effective or impaired wound healing response. An indicator for healing would be of great value to assess disease severity and progression of the chronic wound, and might serve as predictive indicator for the efficacy of a certain therapy regime. This work was supported by the German Research Society (FOR 265)." @default.
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• W2012536700 title "Increased Levels of the Soluble Variant of the Vascular Endothelial Growth Factor Receptor VEGFR-1 Are Associated with a Poor Prognosis in Wound Healing" @default.
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