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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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Model depicting steps in the angiogenic process affected by defective β3 integrin as exemplified by the DiYF mouse. Although impaired β3 function in the DiYF mouse does not affect the mobilization of BMDCs from the BM niche, it weakens adhesion and decreases migration functions, which, in turn, reduce the overall recruitment and retention of BMDCs, resulting in elevated levels of circulating CXCR4+ BMDCs. This leads to dampened vascular sprouting and an inhibition of angiogenesis. Defective endothelial cell function in DiYF mice appears to play a recessive role in this process. Low levels of SDF-1, a result of this angiogenic defect, further potentiate the reduced recruitment and retention of CXCR4+ cells.
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fig8: Model depicting steps in the angiogenic process affected by defective β3 integrin as exemplified by the DiYF mouse. Although impaired β3 function in the DiYF mouse does not affect the mobilization of BMDCs from the BM niche, it weakens adhesion and decreases migration functions, which, in turn, reduce the overall recruitment and retention of BMDCs, resulting in elevated levels of circulating CXCR4+ BMDCs. This leads to dampened vascular sprouting and an inhibition of angiogenesis. Defective endothelial cell function in DiYF mice appears to play a recessive role in this process. Low levels of SDF-1, a result of this angiogenic defect, further potentiate the reduced recruitment and retention of CXCR4+ cells.

Mentions: Our previous studies showed that defective β3 integrin signaling in DiYF mice resulted in inhibition of tumor growth and angiogenesis in vivo and impaired endothelial cell responses in vitro (Mahabeleshwar et al., 2006). The present study was initiated as a result of a preliminary finding wherein transplantation of WT BM completely rescued defective angiogenesis in DiYF mice. The findings presented in this paper are depicted in Fig. 8 with the key points summarized as follows. The course of tumor- and wound-associated angiogenic responses are dependent on BM cell β3 integrin function and not resident host tissue. Defects in platelet function stemming from the DiYF mutation are not causative of the angiogenic defects displayed by DiYF mice. The recruitment of DiYF BMDCs to sites of neovascularization is compromised compared with that of WT BMDCs. The majority of recruited BMDCs are negative for endothelial or smooth muscle cell markers, but appear to express CD45, Gr1, CD3, and CXCR4, indicating the hematopoietic origin of these cells. SDF-1 levels are reduced in tumors grown in DiYF mice compared with WT, a condition corrected by BMT. Impaired β3 integrin activity has little effect on the process of BMDC release into the circulation; however, DiYF CXCR4+ BMDCs exhibit defective adhesion and transmigration through endothelial monolayers compared with WT counterparts. These data indicate that β3 integrin activity on circulating CXCR4+ BMDCs, but not β3 integrin on resident endothelial cells or platelets, plays a governing role in angiogenesis through regulating BMDC recruitment to angiogenic sites and adherence to and transmigration through endothelium.


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)

Model depicting steps in the angiogenic process affected by defective β3 integrin as exemplified by the DiYF mouse. Although impaired β3 function in the DiYF mouse does not affect the mobilization of BMDCs from the BM niche, it weakens adhesion and decreases migration functions, which, in turn, reduce the overall recruitment and retention of BMDCs, resulting in elevated levels of circulating CXCR4+ BMDCs. This leads to dampened vascular sprouting and an inhibition of angiogenesis. Defective endothelial cell function in DiYF mice appears to play a recessive role in this process. Low levels of SDF-1, a result of this angiogenic defect, further potentiate the reduced recruitment and retention of CXCR4+ cells.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Model depicting steps in the angiogenic process affected by defective β3 integrin as exemplified by the DiYF mouse. Although impaired β3 function in the DiYF mouse does not affect the mobilization of BMDCs from the BM niche, it weakens adhesion and decreases migration functions, which, in turn, reduce the overall recruitment and retention of BMDCs, resulting in elevated levels of circulating CXCR4+ BMDCs. This leads to dampened vascular sprouting and an inhibition of angiogenesis. Defective endothelial cell function in DiYF mice appears to play a recessive role in this process. Low levels of SDF-1, a result of this angiogenic defect, further potentiate the reduced recruitment and retention of CXCR4+ cells.
Mentions: Our previous studies showed that defective β3 integrin signaling in DiYF mice resulted in inhibition of tumor growth and angiogenesis in vivo and impaired endothelial cell responses in vitro (Mahabeleshwar et al., 2006). The present study was initiated as a result of a preliminary finding wherein transplantation of WT BM completely rescued defective angiogenesis in DiYF mice. The findings presented in this paper are depicted in Fig. 8 with the key points summarized as follows. The course of tumor- and wound-associated angiogenic responses are dependent on BM cell β3 integrin function and not resident host tissue. Defects in platelet function stemming from the DiYF mutation are not causative of the angiogenic defects displayed by DiYF mice. The recruitment of DiYF BMDCs to sites of neovascularization is compromised compared with that of WT BMDCs. The majority of recruited BMDCs are negative for endothelial or smooth muscle cell markers, but appear to express CD45, Gr1, CD3, and CXCR4, indicating the hematopoietic origin of these cells. SDF-1 levels are reduced in tumors grown in DiYF mice compared with WT, a condition corrected by BMT. Impaired β3 integrin activity has little effect on the process of BMDC release into the circulation; however, DiYF CXCR4+ BMDCs exhibit defective adhesion and transmigration through endothelial monolayers compared with WT counterparts. These data indicate that β3 integrin activity on circulating CXCR4+ BMDCs, but not β3 integrin on resident endothelial cells or platelets, plays a governing role in angiogenesis through regulating BMDC recruitment to angiogenic sites and adherence to and transmigration through endothelium.

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