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The angiogenic response is dictated by beta3 integrin on bone marrow-derived cells.

Feng W, McCabe NP, Mahabeleshwar GH, Somanath PR, Phillips DR, Byzova TV - J. Cell Biol. (2008)

Bottom Line: Angiogenesis is dependent on the coordinated action of numerous cell types.Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization.Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

ABSTRACT
Angiogenesis is dependent on the coordinated action of numerous cell types. A key adhesion molecule expressed by these cells is the alpha(v)beta(3) integrin. Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization. Using knockin mice expressing functionally stunted beta(3) integrin, we show that bone marrow transplantation rescues impaired angiogenesis in these mice by normalizing BMDC recruitment. We demonstrate that alpha(v)beta(3) integrin enhances BMDC recruitment and retention at angiogenic sites by mediating cellular adhesion and transmigration of BMDCs through the endothelial monolayer but not their release from the bone niche. Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

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Infiltration of BMDCs is β3 integrin dependent. (A) Immunofluorescent detection of SMA (red) and GFP (green) on B16F10 tumor tissues in WT mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 100 μm. (B) Quantification of GFP-positive cells in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Data represent mean ± SEM. *, P < 0.05; **, P < 0.01. (C) Quantification of GFP-positive cells in wound tissue (day 7) sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Data represent mean ± SEM. *, P < 0.05; **, P < 0.01.
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fig3: Infiltration of BMDCs is β3 integrin dependent. (A) Immunofluorescent detection of SMA (red) and GFP (green) on B16F10 tumor tissues in WT mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 100 μm. (B) Quantification of GFP-positive cells in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Data represent mean ± SEM. *, P < 0.05; **, P < 0.01. (C) Quantification of GFP-positive cells in wound tissue (day 7) sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Data represent mean ± SEM. *, P < 0.05; **, P < 0.01.

Mentions: Analysis of B16F10 tumors formed in chimeric mice revealed large numbers of GFP+ cells located within the tumor periphery and in the vicinity of tumor vasculature (Fig. 3 A). GFP+ cell numbers were elevated in WT/GFP→WT and WT/GFP→DiYF mice compared with those from DiYF/GFP→WT mice (Fig. S2, available at http://www.jcb.org/cgi/content/full/jcb.200802179/DC1). Importantly, there was no significant difference in the presence of GFP+ cells in tumors from WT/GFP→WT and WT/GFP→DiYF mice (Fig. 3 B), indicating that recruitment of BMDCs and not host vasculature deficiencies are responsible for the impaired angiogenesis exhibited by DiYF mice. These findings were confirmed by assessing infiltration of BMDCs into healing wounds 7 d after wound initiation. As shown previously (Fig. 1 C, bottom right), histological analysis of wound tissues at this time point revealed almost complete wound closure and vascular similarities in WT and DiFY mice. Similar to our tumor model, recruitment of GFP+ cells to wound tissues was impaired in DiYF/GFP→WT mice compared with mice receiving WT/GFP marrow regardless of genotype (Fig. 3 C). In fact, there was no significant difference in the presence of GFP+ cells in wound tissues of WT/GFP→WT and WT/GFP→DiYF mice. Results of our tumor and wound studies emphasize the importance of BMDCs in angiogenic processes and indicate that β3 integrin function is essential for BMDC recruitment to sites of neovascularization.


The angiogenic response is dictated by beta3 integrin on bone marrow-derived cells.

Feng W, McCabe NP, Mahabeleshwar GH, Somanath PR, Phillips DR, Byzova TV - J. Cell Biol. (2008)

Infiltration of BMDCs is β3 integrin dependent. (A) Immunofluorescent detection of SMA (red) and GFP (green) on B16F10 tumor tissues in WT mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 100 μm. (B) Quantification of GFP-positive cells in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Data represent mean ± SEM. *, P < 0.05; **, P < 0.01. (C) Quantification of GFP-positive cells in wound tissue (day 7) sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Data represent mean ± SEM. *, P < 0.05; **, P < 0.01.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2600740&req=5

fig3: Infiltration of BMDCs is β3 integrin dependent. (A) Immunofluorescent detection of SMA (red) and GFP (green) on B16F10 tumor tissues in WT mice after BMT with WT/GFP or DiYF/GFP donor marrow. Bar, 100 μm. (B) Quantification of GFP-positive cells in B16F10 tumor sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Data represent mean ± SEM. *, P < 0.05; **, P < 0.01. (C) Quantification of GFP-positive cells in wound tissue (day 7) sections from WT and DiYF mice after BMT with WT/GFP or DiYF/GFP donor marrow. Data represent mean ± SEM. *, P < 0.05; **, P < 0.01.
Mentions: Analysis of B16F10 tumors formed in chimeric mice revealed large numbers of GFP+ cells located within the tumor periphery and in the vicinity of tumor vasculature (Fig. 3 A). GFP+ cell numbers were elevated in WT/GFP→WT and WT/GFP→DiYF mice compared with those from DiYF/GFP→WT mice (Fig. S2, available at http://www.jcb.org/cgi/content/full/jcb.200802179/DC1). Importantly, there was no significant difference in the presence of GFP+ cells in tumors from WT/GFP→WT and WT/GFP→DiYF mice (Fig. 3 B), indicating that recruitment of BMDCs and not host vasculature deficiencies are responsible for the impaired angiogenesis exhibited by DiYF mice. These findings were confirmed by assessing infiltration of BMDCs into healing wounds 7 d after wound initiation. As shown previously (Fig. 1 C, bottom right), histological analysis of wound tissues at this time point revealed almost complete wound closure and vascular similarities in WT and DiFY mice. Similar to our tumor model, recruitment of GFP+ cells to wound tissues was impaired in DiYF/GFP→WT mice compared with mice receiving WT/GFP marrow regardless of genotype (Fig. 3 C). In fact, there was no significant difference in the presence of GFP+ cells in wound tissues of WT/GFP→WT and WT/GFP→DiYF mice. Results of our tumor and wound studies emphasize the importance of BMDCs in angiogenic processes and indicate that β3 integrin function is essential for BMDC recruitment to sites of neovascularization.

Bottom Line: Angiogenesis is dependent on the coordinated action of numerous cell types.Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization.Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

ABSTRACT
Angiogenesis is dependent on the coordinated action of numerous cell types. A key adhesion molecule expressed by these cells is the alpha(v)beta(3) integrin. Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization. Using knockin mice expressing functionally stunted beta(3) integrin, we show that bone marrow transplantation rescues impaired angiogenesis in these mice by normalizing BMDC recruitment. We demonstrate that alpha(v)beta(3) integrin enhances BMDC recruitment and retention at angiogenic sites by mediating cellular adhesion and transmigration of BMDCs through the endothelial monolayer but not their release from the bone niche. Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

Show MeSH
Related in: MedlinePlus