Bacterial wall products induce downregulation of vascular endothelial growth factor receptors on endothelial cells via a CD14-dependent mechanism: implications for surgical wound healing.

Hdl Handle:
http://hdl.handle.net/10147/209057
Title:
Bacterial wall products induce downregulation of vascular endothelial growth factor receptors on endothelial cells via a CD14-dependent mechanism: implications for surgical wound healing.
Authors:
Power, C; Wang, J H; Sookhai, S; Street, J T; Redmond, H P
Affiliation:
Department of Academic Surgery, Cork University Hospital, Wilton, Cork, Ireland. , cjppower@yahoo.com
Citation:
J Surg Res. 2001 Dec;101(2):138-45.
Journal:
The Journal of surgical research
Issue Date:
3-Feb-2012
URI:
http://hdl.handle.net/10147/209057
DOI:
10.1006/jsre.2001.6270
PubMed ID:
11735268
Abstract:
INTRODUCTION: Vascular endothelial growth factor (VEGF) is a potent mitogenic cytokine which has been identified as the principal polypeptide growth factor influencing endothelial cell (EC) migration and proliferation. Ordered progression of these two processes is an absolute prerequisite for initiating and maintaining the proliferative phase of wound healing. The response of ECs to circulating VEGF is determined by, and directly proportional to, the functional expression of VEGF receptors (KDR/Flt-1) on the EC surface membrane. Systemic sepsis and wound contamination due to bacterial infection are associated with significant retardation of the proliferative phase of wound repair. The effects of the Gram-negative bacterial wall components lipopolysaccharide (LPS) and bacterial lipoprotein (BLP) on VEGF receptor function and expression are unknown and may represent an important biological mechanism predisposing to delayed wound healing in the presence of localized or systemic sepsis. MATERIALS AND METHODS: We designed a series of in vitro experiments investigating this phenomenon and its potential implications for infective wound repair. VEGF receptor density on ECs in the presence of LPS and BLP was assessed using flow cytometry. These parameters were assessed in hypoxic conditions as well as in normoxia. The contribution of CD14 was evaluated using recombinant human (rh) CD14. EC proliferation in response to VEGF was quantified in the presence and absence of LPS and BLP. RESULTS: Flow cytometric analysis revealed that LPS and BLP have profoundly repressive effects on VEGF receptor density in normoxic and, more pertinently, hypoxic conditions. The observed downregulation of constitutive and inducible VEGF receptor expression on ECs was not due to any directly cytotoxic effect of LPS and BLP on ECs, as measured by cell viability and apoptosis assays. We identified a pivotal role for soluble/serum CD14, a highly specific bacterial wall product receptor, in mediating these effects. The decreased VEGF receptor density on ECs accruing from the presence of bacterial wall products resulted in EC hyporesponsiveness to rhVEGF and significant abolition of VEGF-directed EC proliferation. CONCLUSION: These findings suggest that the well-recognized relationship between bacterial sepsis and attenuated wound healing may be due, in part, to the directly suppressive effects of bacterial wall components on EC VEGF receptor expression and, consequently, EC proliferation.
Language:
eng
MeSH:
Antigens, CD14/*physiology; Cell Survival/drug effects; Down-Regulation; Endothelial Growth Factors/pharmacology; Endothelium, Vascular/chemistry/cytology/*drug effects; Humans; Lipopolysaccharides/*toxicity; Lipoproteins/*toxicity; Lymphokines/pharmacology; Receptor Protein-Tyrosine Kinases/*analysis/drug effects; Receptors, Growth Factor/*analysis/drug effects; Receptors, Vascular Endothelial Growth Factor; *Surgical Procedures, Operative; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; *Wound Healing
ISSN:
0022-4804 (Print); 0022-4804 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorPower, Cen_GB
dc.contributor.authorWang, J Hen_GB
dc.contributor.authorSookhai, Sen_GB
dc.contributor.authorStreet, J Ten_GB
dc.contributor.authorRedmond, H Pen_GB
dc.date.accessioned2012-02-03T15:11:06Z-
dc.date.available2012-02-03T15:11:06Z-
dc.date.issued2012-02-03T15:11:06Z-
dc.identifier.citationJ Surg Res. 2001 Dec;101(2):138-45.en_GB
dc.identifier.issn0022-4804 (Print)en_GB
dc.identifier.issn0022-4804 (Linking)en_GB
dc.identifier.pmid11735268en_GB
dc.identifier.doi10.1006/jsre.2001.6270en_GB
dc.identifier.urihttp://hdl.handle.net/10147/209057-
dc.description.abstractINTRODUCTION: Vascular endothelial growth factor (VEGF) is a potent mitogenic cytokine which has been identified as the principal polypeptide growth factor influencing endothelial cell (EC) migration and proliferation. Ordered progression of these two processes is an absolute prerequisite for initiating and maintaining the proliferative phase of wound healing. The response of ECs to circulating VEGF is determined by, and directly proportional to, the functional expression of VEGF receptors (KDR/Flt-1) on the EC surface membrane. Systemic sepsis and wound contamination due to bacterial infection are associated with significant retardation of the proliferative phase of wound repair. The effects of the Gram-negative bacterial wall components lipopolysaccharide (LPS) and bacterial lipoprotein (BLP) on VEGF receptor function and expression are unknown and may represent an important biological mechanism predisposing to delayed wound healing in the presence of localized or systemic sepsis. MATERIALS AND METHODS: We designed a series of in vitro experiments investigating this phenomenon and its potential implications for infective wound repair. VEGF receptor density on ECs in the presence of LPS and BLP was assessed using flow cytometry. These parameters were assessed in hypoxic conditions as well as in normoxia. The contribution of CD14 was evaluated using recombinant human (rh) CD14. EC proliferation in response to VEGF was quantified in the presence and absence of LPS and BLP. RESULTS: Flow cytometric analysis revealed that LPS and BLP have profoundly repressive effects on VEGF receptor density in normoxic and, more pertinently, hypoxic conditions. The observed downregulation of constitutive and inducible VEGF receptor expression on ECs was not due to any directly cytotoxic effect of LPS and BLP on ECs, as measured by cell viability and apoptosis assays. We identified a pivotal role for soluble/serum CD14, a highly specific bacterial wall product receptor, in mediating these effects. The decreased VEGF receptor density on ECs accruing from the presence of bacterial wall products resulted in EC hyporesponsiveness to rhVEGF and significant abolition of VEGF-directed EC proliferation. CONCLUSION: These findings suggest that the well-recognized relationship between bacterial sepsis and attenuated wound healing may be due, in part, to the directly suppressive effects of bacterial wall components on EC VEGF receptor expression and, consequently, EC proliferation.en_GB
dc.language.isoengen_GB
dc.subject.meshAntigens, CD14/*physiologyen_GB
dc.subject.meshCell Survival/drug effectsen_GB
dc.subject.meshDown-Regulationen_GB
dc.subject.meshEndothelial Growth Factors/pharmacologyen_GB
dc.subject.meshEndothelium, Vascular/chemistry/cytology/*drug effectsen_GB
dc.subject.meshHumansen_GB
dc.subject.meshLipopolysaccharides/*toxicityen_GB
dc.subject.meshLipoproteins/*toxicityen_GB
dc.subject.meshLymphokines/pharmacologyen_GB
dc.subject.meshReceptor Protein-Tyrosine Kinases/*analysis/drug effectsen_GB
dc.subject.meshReceptors, Growth Factor/*analysis/drug effectsen_GB
dc.subject.meshReceptors, Vascular Endothelial Growth Factoren_GB
dc.subject.mesh*Surgical Procedures, Operativeen_GB
dc.subject.meshVascular Endothelial Growth Factor Aen_GB
dc.subject.meshVascular Endothelial Growth Factorsen_GB
dc.subject.mesh*Wound Healingen_GB
dc.titleBacterial wall products induce downregulation of vascular endothelial growth factor receptors on endothelial cells via a CD14-dependent mechanism: implications for surgical wound healing.en_GB
dc.contributor.departmentDepartment of Academic Surgery, Cork University Hospital, Wilton, Cork, Ireland. , cjppower@yahoo.comen_GB
dc.identifier.journalThe Journal of surgical researchen_GB
dc.description.provinceMunster-
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