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The Role of Vascular Endothelial Growth Factor Receptor-1 Signaling in the Recovery from Ischemia.

Amano H, Kato S, Ito Y, Eshima K, Ogawa F, Takahashi R, Sekiguchi K, Tamaki H, Sakagami H, Shibuya M, Majima M - PLoS ONE (2015)

Bottom Line: Compared to wild type mice (WT), TK-/- mice had no change in the plasma level of VEGF, but the plasma levels of stromal-derived cell factor 1 (SDF-1) and stem cell factor, as well as the bone marrow (BM) level of pro-matrix metalloproteinase-9 (pro-MMP-9), were significantly reduced.The recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) into peripheral blood and ischemic muscles was also suppressed.Furthermore, WT transplanted with TK-/- BM significantly impaired blood flow recovery more than WT transplanted with WT BM.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.

ABSTRACT
Vascular endothelial growth factor (VEGF) is one of the most potent angiogenesis stimulators. VEGF binds to VEGF receptor 1 (VEGFR1), inducing angiogenesis through the receptor's tyrosine kinase domain (TK), but the mechanism is not well understood. We investigated the role of VEGFR1 tyrosine kinase signaling in angiogenesis using the ischemic hind limb model. Relative to control mice, blood flow recovery was significantly impaired in mice treated with VEGFA-neutralizing antibody. VEGFR1 tyrosine kinase knockout mice (TK-/-) had delayed blood flow recovery from ischemia and impaired angiogenesis, and this phenotype was unaffected by treatment with a VEGFR2 inhibitor. Compared to wild type mice (WT), TK-/- mice had no change in the plasma level of VEGF, but the plasma levels of stromal-derived cell factor 1 (SDF-1) and stem cell factor, as well as the bone marrow (BM) level of pro-matrix metalloproteinase-9 (pro-MMP-9), were significantly reduced. The recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) into peripheral blood and ischemic muscles was also suppressed. Furthermore, WT transplanted with TK-/- BM significantly impaired blood flow recovery more than WT transplanted with WT BM. These results suggest that VEGFR1-TK signaling facilitates angiogenesis by recruiting CXCR4+VEGFR1+ cells from BM.

No MeSH data available.


Related in: MedlinePlus

The effect of VEGFR1TK signaling on hematopoietic cytokine levels and the mobilization of CXCR4+VEGFR1+ cells.Bone marrow level of pro-MMP-9 level (A) and plasma level of SCF (B) on days 0, 1, 3, 5, and 7 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT). (C) Mobilization of CXCR4+VEGFR1+ cells in peripheral blood was impaired in TK-/-, as compared to WT, on day 7 after surgery, as revealed by two-color flow cytometry. (D) Quantification of CXCR4+VEGFR1+ cells in peripheral blood on day 7 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).
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pone.0131445.g006: The effect of VEGFR1TK signaling on hematopoietic cytokine levels and the mobilization of CXCR4+VEGFR1+ cells.Bone marrow level of pro-MMP-9 level (A) and plasma level of SCF (B) on days 0, 1, 3, 5, and 7 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT). (C) Mobilization of CXCR4+VEGFR1+ cells in peripheral blood was impaired in TK-/-, as compared to WT, on day 7 after surgery, as revealed by two-color flow cytometry. (D) Quantification of CXCR4+VEGFR1+ cells in peripheral blood on day 7 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).

Mentions: BM-derived HSCs plays a crucial role in ischemic revascularization [13]. Fig 6A and 6B shows the bone marrow (BM) and plasma levels of hematopoietic cytokines, including pro-MMP-9 and stem cell factor (SCF). BM levels of pro-MMP-9 (Fig 6A) and plasma levels of SCF (Fig 6B) were significantly decreased in TK-/- compared to those of WT on days 1, 3, and 5 (P<0.05). We previously reported that BM-derived CXCR4+VEGFR1+ to gastric ulcer lesions is important for ulcer regeneration [10]. Therefore, we measured the mobilization of CXCR4+VEGFR1+ cells into ischemic muscle tissues using fluorescence-activated cell-sorting analysis (FACS). On day 7, the percentage of CXCR4+VEGFR1+ cells in circulating cells was reduced in TK-/- (WT: 1.87 ± 0.31, TK-/-: 0.63 ± 0.12, P<0.05, Fig 6C). Compared to WT, the total number of CXCR4+VEGFR1+ cells in the ischemic muscle was significantly reduced in TK-/- (WT: 123.8 ± 19.51 cells/field, TK-/-: 94.4 ± 6.8 cells/field, P<0.05, n = 5 per group, P<0.05, Fig 7A and 7B). These findings suggest that VEGFR1-TK signaling helps promote CXCR4+VEGFR1+ mobilization into circulation and ischemic tissue.


The Role of Vascular Endothelial Growth Factor Receptor-1 Signaling in the Recovery from Ischemia.

Amano H, Kato S, Ito Y, Eshima K, Ogawa F, Takahashi R, Sekiguchi K, Tamaki H, Sakagami H, Shibuya M, Majima M - PLoS ONE (2015)

The effect of VEGFR1TK signaling on hematopoietic cytokine levels and the mobilization of CXCR4+VEGFR1+ cells.Bone marrow level of pro-MMP-9 level (A) and plasma level of SCF (B) on days 0, 1, 3, 5, and 7 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT). (C) Mobilization of CXCR4+VEGFR1+ cells in peripheral blood was impaired in TK-/-, as compared to WT, on day 7 after surgery, as revealed by two-color flow cytometry. (D) Quantification of CXCR4+VEGFR1+ cells in peripheral blood on day 7 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4489890&req=5

pone.0131445.g006: The effect of VEGFR1TK signaling on hematopoietic cytokine levels and the mobilization of CXCR4+VEGFR1+ cells.Bone marrow level of pro-MMP-9 level (A) and plasma level of SCF (B) on days 0, 1, 3, 5, and 7 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT). (C) Mobilization of CXCR4+VEGFR1+ cells in peripheral blood was impaired in TK-/-, as compared to WT, on day 7 after surgery, as revealed by two-color flow cytometry. (D) Quantification of CXCR4+VEGFR1+ cells in peripheral blood on day 7 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).
Mentions: BM-derived HSCs plays a crucial role in ischemic revascularization [13]. Fig 6A and 6B shows the bone marrow (BM) and plasma levels of hematopoietic cytokines, including pro-MMP-9 and stem cell factor (SCF). BM levels of pro-MMP-9 (Fig 6A) and plasma levels of SCF (Fig 6B) were significantly decreased in TK-/- compared to those of WT on days 1, 3, and 5 (P<0.05). We previously reported that BM-derived CXCR4+VEGFR1+ to gastric ulcer lesions is important for ulcer regeneration [10]. Therefore, we measured the mobilization of CXCR4+VEGFR1+ cells into ischemic muscle tissues using fluorescence-activated cell-sorting analysis (FACS). On day 7, the percentage of CXCR4+VEGFR1+ cells in circulating cells was reduced in TK-/- (WT: 1.87 ± 0.31, TK-/-: 0.63 ± 0.12, P<0.05, Fig 6C). Compared to WT, the total number of CXCR4+VEGFR1+ cells in the ischemic muscle was significantly reduced in TK-/- (WT: 123.8 ± 19.51 cells/field, TK-/-: 94.4 ± 6.8 cells/field, P<0.05, n = 5 per group, P<0.05, Fig 7A and 7B). These findings suggest that VEGFR1-TK signaling helps promote CXCR4+VEGFR1+ mobilization into circulation and ischemic tissue.

Bottom Line: Compared to wild type mice (WT), TK-/- mice had no change in the plasma level of VEGF, but the plasma levels of stromal-derived cell factor 1 (SDF-1) and stem cell factor, as well as the bone marrow (BM) level of pro-matrix metalloproteinase-9 (pro-MMP-9), were significantly reduced.The recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) into peripheral blood and ischemic muscles was also suppressed.Furthermore, WT transplanted with TK-/- BM significantly impaired blood flow recovery more than WT transplanted with WT BM.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.

ABSTRACT
Vascular endothelial growth factor (VEGF) is one of the most potent angiogenesis stimulators. VEGF binds to VEGF receptor 1 (VEGFR1), inducing angiogenesis through the receptor's tyrosine kinase domain (TK), but the mechanism is not well understood. We investigated the role of VEGFR1 tyrosine kinase signaling in angiogenesis using the ischemic hind limb model. Relative to control mice, blood flow recovery was significantly impaired in mice treated with VEGFA-neutralizing antibody. VEGFR1 tyrosine kinase knockout mice (TK-/-) had delayed blood flow recovery from ischemia and impaired angiogenesis, and this phenotype was unaffected by treatment with a VEGFR2 inhibitor. Compared to wild type mice (WT), TK-/- mice had no change in the plasma level of VEGF, but the plasma levels of stromal-derived cell factor 1 (SDF-1) and stem cell factor, as well as the bone marrow (BM) level of pro-matrix metalloproteinase-9 (pro-MMP-9), were significantly reduced. The recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) into peripheral blood and ischemic muscles was also suppressed. Furthermore, WT transplanted with TK-/- BM significantly impaired blood flow recovery more than WT transplanted with WT BM. These results suggest that VEGFR1-TK signaling facilitates angiogenesis by recruiting CXCR4+VEGFR1+ cells from BM.

No MeSH data available.


Related in: MedlinePlus