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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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The SDF-1/CXCR4 axis regulates angiogenesis in DiYF mice. (A) Levels of SDF-1 in WT and DiYF B16F10 tumors. Data represent mean ± SEM (duplicate measurements of n = 10 [WT] and n = 8 [DiYF] tumors each group). *, P < 0.05. (B) Levels of SDF-1 in WT and DiYF B16F10 tumors after BMT with WT donor marrow. Data represent mean ± SEM (duplicate measurements of n = 6 per group). (C) Immunofluorescent detection of GFP (a, d, and g) and CXCR4 (b, e, and h) along with the merged image (c, f, and i). Sections are of RM1 origin in WT (a–c and g–i) and DiYF (d–f) mice after BMT with WT/GFP (a–f) or DiYF/GFP (g–i) donor marrow. (D) Peripheral blood analysis of β3+ and CXCR4+ cells in nontumor- and B16F10 tumor-bearing WT and DiYF mice. (E) Percentage of circulating CXCR4+ cells in nontumor- and B16F10 tumor-bearing WT and DiYF mice. Data represent mean ± SEM (n = 5 per group). (F) Percentage of circulating CXCR4+β3+ cells in B16F10 tumor-bearing WT and DiYF mice. Data represent mean ± SEM (n = 5 per group). **, P < 0.01.
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fig6: The SDF-1/CXCR4 axis regulates angiogenesis in DiYF mice. (A) Levels of SDF-1 in WT and DiYF B16F10 tumors. Data represent mean ± SEM (duplicate measurements of n = 10 [WT] and n = 8 [DiYF] tumors each group). *, P < 0.05. (B) Levels of SDF-1 in WT and DiYF B16F10 tumors after BMT with WT donor marrow. Data represent mean ± SEM (duplicate measurements of n = 6 per group). (C) Immunofluorescent detection of GFP (a, d, and g) and CXCR4 (b, e, and h) along with the merged image (c, f, and i). Sections are of RM1 origin in WT (a–c and g–i) and DiYF (d–f) mice after BMT with WT/GFP (a–f) or DiYF/GFP (g–i) donor marrow. (D) Peripheral blood analysis of β3+ and CXCR4+ cells in nontumor- and B16F10 tumor-bearing WT and DiYF mice. (E) Percentage of circulating CXCR4+ cells in nontumor- and B16F10 tumor-bearing WT and DiYF mice. Data represent mean ± SEM (n = 5 per group). (F) Percentage of circulating CXCR4+β3+ cells in B16F10 tumor-bearing WT and DiYF mice. Data represent mean ± SEM (n = 5 per group). **, P < 0.01.

Mentions: A key factor for BMDC retention in angiogenic tissues is SDF-1, a chemokine produced by, but not limited to, mural cells such as perivascular fibroblasts and smooth muscle cells (Kucia et al., 2005; Orimo et al., 2005; Grunewald et al., 2006). DiYF angiogenic defects are accompanied by reduced numbers of SMA-positive cells, which may result in decreased levels of local and systemic SDF-1. Therefore, the SDF-1 content in tumors and plasma from WT and DiYF mice were determined. Although SDF-1 plasma levels in tumor-bearing WT and DiYF mice were closely matched (Fig. S4 A, available at http://www.jcb.org/cgi/content/full/jcb.200802179/DC1), tumor concentrations of SDF-1 in DiYF mice were ∼50% less than that of WT mice (Fig. 6 A). SDF-1 levels in leukocytes, BM cells, endothelial cell culture medium, and smooth muscle cell culture medium were similar for WT and DiYF mice (Fig. S4, B and C). Transplantation of WT marrow into DiYF mice normalized the levels of SDF-1 in tumor tissues (Fig. 6 B).


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)

The SDF-1/CXCR4 axis regulates angiogenesis in DiYF mice. (A) Levels of SDF-1 in WT and DiYF B16F10 tumors. Data represent mean ± SEM (duplicate measurements of n = 10 [WT] and n = 8 [DiYF] tumors each group). *, P < 0.05. (B) Levels of SDF-1 in WT and DiYF B16F10 tumors after BMT with WT donor marrow. Data represent mean ± SEM (duplicate measurements of n = 6 per group). (C) Immunofluorescent detection of GFP (a, d, and g) and CXCR4 (b, e, and h) along with the merged image (c, f, and i). Sections are of RM1 origin in WT (a–c and g–i) and DiYF (d–f) mice after BMT with WT/GFP (a–f) or DiYF/GFP (g–i) donor marrow. (D) Peripheral blood analysis of β3+ and CXCR4+ cells in nontumor- and B16F10 tumor-bearing WT and DiYF mice. (E) Percentage of circulating CXCR4+ cells in nontumor- and B16F10 tumor-bearing WT and DiYF mice. Data represent mean ± SEM (n = 5 per group). (F) Percentage of circulating CXCR4+β3+ cells in B16F10 tumor-bearing WT and DiYF mice. Data represent mean ± SEM (n = 5 per group). **, P < 0.01.
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fig6: The SDF-1/CXCR4 axis regulates angiogenesis in DiYF mice. (A) Levels of SDF-1 in WT and DiYF B16F10 tumors. Data represent mean ± SEM (duplicate measurements of n = 10 [WT] and n = 8 [DiYF] tumors each group). *, P < 0.05. (B) Levels of SDF-1 in WT and DiYF B16F10 tumors after BMT with WT donor marrow. Data represent mean ± SEM (duplicate measurements of n = 6 per group). (C) Immunofluorescent detection of GFP (a, d, and g) and CXCR4 (b, e, and h) along with the merged image (c, f, and i). Sections are of RM1 origin in WT (a–c and g–i) and DiYF (d–f) mice after BMT with WT/GFP (a–f) or DiYF/GFP (g–i) donor marrow. (D) Peripheral blood analysis of β3+ and CXCR4+ cells in nontumor- and B16F10 tumor-bearing WT and DiYF mice. (E) Percentage of circulating CXCR4+ cells in nontumor- and B16F10 tumor-bearing WT and DiYF mice. Data represent mean ± SEM (n = 5 per group). (F) Percentage of circulating CXCR4+β3+ cells in B16F10 tumor-bearing WT and DiYF mice. Data represent mean ± SEM (n = 5 per group). **, P < 0.01.
Mentions: A key factor for BMDC retention in angiogenic tissues is SDF-1, a chemokine produced by, but not limited to, mural cells such as perivascular fibroblasts and smooth muscle cells (Kucia et al., 2005; Orimo et al., 2005; Grunewald et al., 2006). DiYF angiogenic defects are accompanied by reduced numbers of SMA-positive cells, which may result in decreased levels of local and systemic SDF-1. Therefore, the SDF-1 content in tumors and plasma from WT and DiYF mice were determined. Although SDF-1 plasma levels in tumor-bearing WT and DiYF mice were closely matched (Fig. S4 A, available at http://www.jcb.org/cgi/content/full/jcb.200802179/DC1), tumor concentrations of SDF-1 in DiYF mice were ∼50% less than that of WT mice (Fig. 6 A). SDF-1 levels in leukocytes, BM cells, endothelial cell culture medium, and smooth muscle cell culture medium were similar for WT and DiYF mice (Fig. S4, B and C). Transplantation of WT marrow into DiYF mice normalized the levels of SDF-1 in tumor tissues (Fig. 6 B).

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