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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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Circulating CXCR4+ cells from DiYF mice exhibit impaired adhesion to and migration through endothelium. (A) Relative number of adherent CXCR4+ cells from the peripheral blood of nontumor- and B16F10 tumor-bearing WT and DiYF after plating on an endothelial monolayer. Data represent mean ± SEM and are representative of nine independent experiments. (B) Relative number of endothelial monolayer transmigrating CXCR4+ cells from the peripheral blood of nontumor- and B16F10 tumor-bearing WT and DiYF after plating on an endothelial monolayer. Data represent mean ± SEM and are representative of five independent experiments. **, P < 0.01.
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fig7: Circulating CXCR4+ cells from DiYF mice exhibit impaired adhesion to and migration through endothelium. (A) Relative number of adherent CXCR4+ cells from the peripheral blood of nontumor- and B16F10 tumor-bearing WT and DiYF after plating on an endothelial monolayer. Data represent mean ± SEM and are representative of nine independent experiments. (B) Relative number of endothelial monolayer transmigrating CXCR4+ cells from the peripheral blood of nontumor- and B16F10 tumor-bearing WT and DiYF after plating on an endothelial monolayer. Data represent mean ± SEM and are representative of five independent experiments. **, P < 0.01.

Mentions: Many integrins are known to control cellular adhesion and transmigration through endothelium, which, in turn, controls lymphocyte homing and subsequent immune responses (Mackay, 1995). It is possible that the DiYF mutation of β3 integrins could affect adhesion of circulating BM-derived CXCR4+ cells to the endothelial lining as well as their transmigration. To investigate this possibility, CXCR4+ cells were isolated from peripheral blood of WT and DiYF mice and their ability to adhere and transmigrate through an endothelial monolayer was assessed. The presence of tumors promoted a threefold increase in the adhesion of WT CXCR4+ cells to endothelium but had no effect on the adherence of DiYF CXCR4+ cells (Fig. 7 A). Likewise, DiYF CXCR4+ cells had an impaired ability to transmigrate through the endothelial monolayer compared with WT CXCR4+ cells (Fig. 7 B). However, WT CXCR4+ cell migration was twofold that of DiYF cells without tumor and increased in the presence of tumor, whereas the presence of tumor had no notable effect on DiYF CXCR4+ cell migration. These data illustrate the importance of fully functional β3 integrin signaling in processes associated with recruitment into and retention of recruited BM-derived CXCR4+ cells at angiogenic sites.


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)

Circulating CXCR4+ cells from DiYF mice exhibit impaired adhesion to and migration through endothelium. (A) Relative number of adherent CXCR4+ cells from the peripheral blood of nontumor- and B16F10 tumor-bearing WT and DiYF after plating on an endothelial monolayer. Data represent mean ± SEM and are representative of nine independent experiments. (B) Relative number of endothelial monolayer transmigrating CXCR4+ cells from the peripheral blood of nontumor- and B16F10 tumor-bearing WT and DiYF after plating on an endothelial monolayer. Data represent mean ± SEM and are representative of five independent experiments. **, P < 0.01.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Circulating CXCR4+ cells from DiYF mice exhibit impaired adhesion to and migration through endothelium. (A) Relative number of adherent CXCR4+ cells from the peripheral blood of nontumor- and B16F10 tumor-bearing WT and DiYF after plating on an endothelial monolayer. Data represent mean ± SEM and are representative of nine independent experiments. (B) Relative number of endothelial monolayer transmigrating CXCR4+ cells from the peripheral blood of nontumor- and B16F10 tumor-bearing WT and DiYF after plating on an endothelial monolayer. Data represent mean ± SEM and are representative of five independent experiments. **, P < 0.01.
Mentions: Many integrins are known to control cellular adhesion and transmigration through endothelium, which, in turn, controls lymphocyte homing and subsequent immune responses (Mackay, 1995). It is possible that the DiYF mutation of β3 integrins could affect adhesion of circulating BM-derived CXCR4+ cells to the endothelial lining as well as their transmigration. To investigate this possibility, CXCR4+ cells were isolated from peripheral blood of WT and DiYF mice and their ability to adhere and transmigrate through an endothelial monolayer was assessed. The presence of tumors promoted a threefold increase in the adhesion of WT CXCR4+ cells to endothelium but had no effect on the adherence of DiYF CXCR4+ cells (Fig. 7 A). Likewise, DiYF CXCR4+ cells had an impaired ability to transmigrate through the endothelial monolayer compared with WT CXCR4+ cells (Fig. 7 B). However, WT CXCR4+ cell migration was twofold that of DiYF cells without tumor and increased in the presence of tumor, whereas the presence of tumor had no notable effect on DiYF CXCR4+ cell migration. These data illustrate the importance of fully functional β3 integrin signaling in processes associated with recruitment into and retention of recruited BM-derived CXCR4+ cells at angiogenic sites.

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