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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 angiogenic phenotype of DiYF mice is BM dependent. (A) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT and DiYF mice (left). Microvessel density in B16F10 tumors from WT and DiYF mice (right). Bar, 100 μm. Data represent mean ± SEM. **, P < 0.01. (B) SMA-positive microvessel density of B16F10 tumor sections from WT and DiYF mice. Data represent mean ± SEM. *, P < 0.05. (C) von Willebrand factor (vWF)–positive microvessel density of tissue sections from 10-d-old wounds of WT and DiYF mice. Data represent mean ± SEM. *, P < 0.05. (D) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT donor marrow (left). Bar, 200 μm. Insets depict similarities in vessel cellular organization. CD31 and NG2 microvessel density in B16F10 tumors from WT and DiYF mice after BMT with WT donor marrow (right). Data represent mean ± SEM. (E) SMA microvessel density in B16F10 tumors from WT and DiYF mice after BMT with WT donor marrow. Data represent mean ± SEM. (F) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT mice after BMT with WT or DiYF donor marrow (left). Bar, 200 μm. CD31 and NG2 microvessel area in B16F10 tumors from WT mice after BMT with WT or DiYF donor marrow (right). Data represent mean ± SEM. *, P < 0.05. (G) SMA microvessel density in B16F10 tumors from WT mice after BMT with WT and DiYF donor marrow. Data represent mean ± SEM. *; P < 0.05.
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fig2: The angiogenic phenotype of DiYF mice is BM dependent. (A) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT and DiYF mice (left). Microvessel density in B16F10 tumors from WT and DiYF mice (right). Bar, 100 μm. Data represent mean ± SEM. **, P < 0.01. (B) SMA-positive microvessel density of B16F10 tumor sections from WT and DiYF mice. Data represent mean ± SEM. *, P < 0.05. (C) von Willebrand factor (vWF)–positive microvessel density of tissue sections from 10-d-old wounds of WT and DiYF mice. Data represent mean ± SEM. *, P < 0.05. (D) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT donor marrow (left). Bar, 200 μm. Insets depict similarities in vessel cellular organization. CD31 and NG2 microvessel density in B16F10 tumors from WT and DiYF mice after BMT with WT donor marrow (right). Data represent mean ± SEM. (E) SMA microvessel density in B16F10 tumors from WT and DiYF mice after BMT with WT donor marrow. Data represent mean ± SEM. (F) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT mice after BMT with WT or DiYF donor marrow (left). Bar, 200 μm. CD31 and NG2 microvessel area in B16F10 tumors from WT mice after BMT with WT or DiYF donor marrow (right). Data represent mean ± SEM. *, P < 0.05. (G) SMA microvessel density in B16F10 tumors from WT mice after BMT with WT and DiYF donor marrow. Data represent mean ± SEM. *; P < 0.05.

Mentions: Having previously reported angiogenic defects in implanted tumors of DiYF mice (Mahabeleshwar et al., 2006), we further investigated the phenotype of these defects and whether they were BM dependent. Histological examination of B16F10 and RM1 tumor, as well as wound sections, illuminates this angiogenic defect (Fig. S1 A, available at http://www.jcb.org/cgi/content/full/jcb.200802179/DC1). Double staining of B16F10 tumor sections with the endothelial cell marker CD31 and the pericyte marker neuro/glial cell 2 chondroitin proteoglycan (NG2) revealed a substantial (greater than threefold) decrease in both CD31- and NG2-positive blood vessel densities in tumors of DiYF hosts (Fig. 2 A). Total VE cell and pericytes positive areas in tumor tissues were also decreased (by 55 and 45%, respectively) in DiYF hosts (Fig. S1 B, top left) with no accompanying differences in blood vessel size (Fig. S1 B, top right). Colocalization of endothelial cells and pericytes in tumor vasculature revealed no morphological differences between B16F10 tumor sections regardless of host genotype. A reduction in the basement membrane protein laminin was also evident in tumors of DiYF hosts (Fig. S1 B, middle left). In addition, smooth muscle actin (SMA), a myofibroblast and adult smooth muscle pericyte marker, exhibited a fourfold decrease in DiYF B16F10 tumor sections compared with WT mice (Fig. 2 B). Immunohistochemical analysis revealed a decrease in von Willebrand factor vessel density (Fig. 2 C) and area (Fig. S1 B, bottom) in DiYF mice wound tissues compared with WT mice. Reduced staining for these vascular markers has previously been shown in RM1 tumor sections (Mahabeleshwar et al., 2006) and is consistent with that of healing wounds of DiYF mice (Fig. 2 C and Fig. S1 B, middle right) as well. These data illustrate the angiogenic defects of implanted tumors and wounds of DiYF mice.


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 angiogenic phenotype of DiYF mice is BM dependent. (A) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT and DiYF mice (left). Microvessel density in B16F10 tumors from WT and DiYF mice (right). Bar, 100 μm. Data represent mean ± SEM. **, P < 0.01. (B) SMA-positive microvessel density of B16F10 tumor sections from WT and DiYF mice. Data represent mean ± SEM. *, P < 0.05. (C) von Willebrand factor (vWF)–positive microvessel density of tissue sections from 10-d-old wounds of WT and DiYF mice. Data represent mean ± SEM. *, P < 0.05. (D) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT donor marrow (left). Bar, 200 μm. Insets depict similarities in vessel cellular organization. CD31 and NG2 microvessel density in B16F10 tumors from WT and DiYF mice after BMT with WT donor marrow (right). Data represent mean ± SEM. (E) SMA microvessel density in B16F10 tumors from WT and DiYF mice after BMT with WT donor marrow. Data represent mean ± SEM. (F) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT mice after BMT with WT or DiYF donor marrow (left). Bar, 200 μm. CD31 and NG2 microvessel area in B16F10 tumors from WT mice after BMT with WT or DiYF donor marrow (right). Data represent mean ± SEM. *, P < 0.05. (G) SMA microvessel density in B16F10 tumors from WT mice after BMT with WT and DiYF donor marrow. Data represent mean ± SEM. *; P < 0.05.
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fig2: The angiogenic phenotype of DiYF mice is BM dependent. (A) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT and DiYF mice (left). Microvessel density in B16F10 tumors from WT and DiYF mice (right). Bar, 100 μm. Data represent mean ± SEM. **, P < 0.01. (B) SMA-positive microvessel density of B16F10 tumor sections from WT and DiYF mice. Data represent mean ± SEM. *, P < 0.05. (C) von Willebrand factor (vWF)–positive microvessel density of tissue sections from 10-d-old wounds of WT and DiYF mice. Data represent mean ± SEM. *, P < 0.05. (D) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT and DiYF mice after BMT with WT donor marrow (left). Bar, 200 μm. Insets depict similarities in vessel cellular organization. CD31 and NG2 microvessel density in B16F10 tumors from WT and DiYF mice after BMT with WT donor marrow (right). Data represent mean ± SEM. (E) SMA microvessel density in B16F10 tumors from WT and DiYF mice after BMT with WT donor marrow. Data represent mean ± SEM. (F) Immunofluorescent detection of CD31 (red) and NG2 (green) in B16F10 tumor sections from WT mice after BMT with WT or DiYF donor marrow (left). Bar, 200 μm. CD31 and NG2 microvessel area in B16F10 tumors from WT mice after BMT with WT or DiYF donor marrow (right). Data represent mean ± SEM. *, P < 0.05. (G) SMA microvessel density in B16F10 tumors from WT mice after BMT with WT and DiYF donor marrow. Data represent mean ± SEM. *; P < 0.05.
Mentions: Having previously reported angiogenic defects in implanted tumors of DiYF mice (Mahabeleshwar et al., 2006), we further investigated the phenotype of these defects and whether they were BM dependent. Histological examination of B16F10 and RM1 tumor, as well as wound sections, illuminates this angiogenic defect (Fig. S1 A, available at http://www.jcb.org/cgi/content/full/jcb.200802179/DC1). Double staining of B16F10 tumor sections with the endothelial cell marker CD31 and the pericyte marker neuro/glial cell 2 chondroitin proteoglycan (NG2) revealed a substantial (greater than threefold) decrease in both CD31- and NG2-positive blood vessel densities in tumors of DiYF hosts (Fig. 2 A). Total VE cell and pericytes positive areas in tumor tissues were also decreased (by 55 and 45%, respectively) in DiYF hosts (Fig. S1 B, top left) with no accompanying differences in blood vessel size (Fig. S1 B, top right). Colocalization of endothelial cells and pericytes in tumor vasculature revealed no morphological differences between B16F10 tumor sections regardless of host genotype. A reduction in the basement membrane protein laminin was also evident in tumors of DiYF hosts (Fig. S1 B, middle left). In addition, smooth muscle actin (SMA), a myofibroblast and adult smooth muscle pericyte marker, exhibited a fourfold decrease in DiYF B16F10 tumor sections compared with WT mice (Fig. 2 B). Immunohistochemical analysis revealed a decrease in von Willebrand factor vessel density (Fig. 2 C) and area (Fig. S1 B, bottom) in DiYF mice wound tissues compared with WT mice. Reduced staining for these vascular markers has previously been shown in RM1 tumor sections (Mahabeleshwar et al., 2006) and is consistent with that of healing wounds of DiYF mice (Fig. 2 C and Fig. S1 B, middle right) as well. These data illustrate the angiogenic defects of implanted tumors and wounds of DiYF mice.

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