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Published on: July 4, 2018
Platelet-derived growth factor BB-mediated normalization of dermal interstitial fluid pressure after mast cell
Asa Lidén1, Ansgar Berg, Torbjørn Nedrebø
1Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden.
Insights
Platelet-derived growth factor (PDGF)-BB normalizes interstitial fluid pressure during inflammation. This involves alphaVbeta3 integrin, which mediates tensile forces in connective tissue cells.
Area of Science:
- Integrin biology
- Connective tissue physiology
- Inflammatory response
Background:
- Interstitial fluid pressure (PIF) is crucial for regulating fluid balance in tissues.
- Cell-mediated control of PIF is essential for maintaining normal tissue fluid content.
- Beta1 integrins contribute to dermal PIF by mediating cellular tensile strength on the extracellular matrix.
Purpose of the Study:
- To investigate the role of integrins in regulating interstitial fluid pressure during inflammatory responses.
- To elucidate the mechanism by which platelet-derived growth factor-BB (PDGF-BB) normalizes PIF.
- To identify the specific integrins involved in PDGF-BB-mediated PIF regulation.
Main Methods:
- Utilized mouse models, including beta3-integrin-negative mice.
- Administered anti-integrin antibodies (anti-beta1 and anti-beta3) and cyclic RGD peptides.
- Assessed PIF changes following mast cell degranulation and anaphylaxis.
- Evaluated collagen gel contraction by fibroblasts with varying integrin expression.
Main Results:
- PDGF-BB normalized PIF reduced by anaphylaxis.
- Anti-beta3 integrin antibodies and RGD peptides blocked PDGF-BB's ability to normalize PIF.
- PDGF-BB failed to normalize PIF in beta3-negative mice.
- Anti-beta1 integrin antibodies reduced PIF in normal dermis but did not affect PDGF-BB's normalization effect.
- Collagen gel contraction was dependent on alphaVbeta3 integrin, particularly in the presence of PDGF-BB.
Conclusions:
- AlphaVbeta3 integrin plays a critical role in controlling PIF during inflammatory reactions.
- PDGF-BB stimulates connective tissue cells to generate tensile forces through alphaVbeta3 integrin during inflammation.
- This study reveals a novel in vivo function for alphaVbeta3 integrin in regulating fluid dynamics during inflammation.
Abstract:
Interstitial fluid pressure (PIF) is one of the determinants of transcapillary fluid flux and thereby interstitial fluid volume. Cell-mediated control of PIF regulates fluid content in the loose interstitial connective tissues that surround the capillary bed. To maintain a normal PIF in dermis, beta1 integrins mediate the tensile strength applied by connective tissue cells on the extracellular matrix. Platelet-derived growth factor (PDGF)-BB normalizes anaphylaxis-induced reduction of PIF. Anti-beta3 integrin IgG and a cyclic RGD peptide that inhibits the alphaVbeta3 integrin blocked the ability of PDGF-BB to normalize the lowered PIF resulting from mast cell degranulation. PDGF-BB was unable to normalize PIF lowered as a result of mast cell degranulation in beta3-negative mice. Monoclonal anti-beta3 integrin IgG had no effect on PIF in normal mouse dermis. In contrast, administration of anti-beta1 integrin IgM lowered PIF in normal dermis but had no effect on PDGF-BB-induced normalization of PIF after anaphylaxis. Furthermore, collagen gel contraction mediated by wild-type mouse embryonal fibroblasts were only marginally affected by function-blocking anti-beta1 integrin antibodies, especially in the presence of PDGF-BB. In contrast, contraction mediated by alphaV-negative mouse embryonic fibroblasts was completely blocked by anti-beta1 integrin antibodies, even after stimulation with PDGF-BB. These results show a previously unrecognized in vivo function for the alphaVbeta3 integrin, as a participant in the control of PIF during inflammatory reactions. Furthermore, our data demonstrate that PDGF-BB induces connective tissue cells to generate tensile forces via alphaVbeta3 during such reactions.
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