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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

Role of VEGF and SDF-1 signaling in recovery from ischemic condition.(A) The expression of VEGF in ischemic muscle on days 0 and 1 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(B) The concentration of VEGF in peripheral blood on day 0 and day 1 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).(C) The expression of SDF-1 in ischemic muscle on day 0 and day 3 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(D) The concentration of SDF-1 in peripheral blood on days 0, 1, 3, and 5 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).(E) The expression of CXCR4 in ischemic muscle on day 0 and 1 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(F) Ischemic reperfusion was suppressed by CXCR4 antibody treatment in WT, but not in TK-/- on day 28 after surgical treatment. Data are means ± SD from n = 6 mice/group. *P<0.05 versus control (IgG).
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pone.0131445.g005: Role of VEGF and SDF-1 signaling in recovery from ischemic condition.(A) The expression of VEGF in ischemic muscle on days 0 and 1 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(B) The concentration of VEGF in peripheral blood on day 0 and day 1 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).(C) The expression of SDF-1 in ischemic muscle on day 0 and day 3 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(D) The concentration of SDF-1 in peripheral blood on days 0, 1, 3, and 5 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).(E) The expression of CXCR4 in ischemic muscle on day 0 and 1 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(F) Ischemic reperfusion was suppressed by CXCR4 antibody treatment in WT, but not in TK-/- on day 28 after surgical treatment. Data are means ± SD from n = 6 mice/group. *P<0.05 versus control (IgG).

Mentions: The growth of granulation tissue and the generation of new microvessels through angiogenesis are stimulated by angiogenesis-stimulating factors, VEGF-A and SDF-1. VEGF and SDF-1 mobilize BM-derived VEGFR1+ to promote tumor growth [13,14]. The mRNA level of VEGFA (Fig 5A) and the plasma level of VEGF in both WT and TK-/- were significantly elevated on day 1 relative to day 0; however, there was no difference between the groups on day 1 (147.04 ± 25.2 pg/mL vs. 155.75 ± 38.06 pg/mL, respectively; P = 0.716, n = 5 per group, Fig 5B). By contrast, the mRNA level of SDF-1 (Fig 5C) and the plasma level of SDF-1 were significantly lower in TK-/- than in WT on day 3 (0.72 ± 0.12 ng/mL vs. 1.10 ± 0.15 ng/mL, respectively; P<0.05, n = 5 per group) and day 5 (0.90 ± 0.10 ng/mL vs. 1.39 ± 0.07 ng/mL, respectively; P<0.05, n = 5 per group, Fig 5D). Moreover, the expression of CXCR4, the specific ligand for SDF-1, was significantly suppressed in TK-/- (Fig 5E).


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)

Role of VEGF and SDF-1 signaling in recovery from ischemic condition.(A) The expression of VEGF in ischemic muscle on days 0 and 1 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(B) The concentration of VEGF in peripheral blood on day 0 and day 1 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).(C) The expression of SDF-1 in ischemic muscle on day 0 and day 3 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(D) The concentration of SDF-1 in peripheral blood on days 0, 1, 3, and 5 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).(E) The expression of CXCR4 in ischemic muscle on day 0 and 1 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(F) Ischemic reperfusion was suppressed by CXCR4 antibody treatment in WT, but not in TK-/- on day 28 after surgical treatment. Data are means ± SD from n = 6 mice/group. *P<0.05 versus control (IgG).
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Related In: Results  -  Collection

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pone.0131445.g005: Role of VEGF and SDF-1 signaling in recovery from ischemic condition.(A) The expression of VEGF in ischemic muscle on days 0 and 1 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(B) The concentration of VEGF in peripheral blood on day 0 and day 1 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).(C) The expression of SDF-1 in ischemic muscle on day 0 and day 3 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(D) The concentration of SDF-1 in peripheral blood on days 0, 1, 3, and 5 after surgery. Data are means ± SD from n = 4–5 mice/group. *P<0.05 versus control (WT).(E) The expression of CXCR4 in ischemic muscle on day 0 and 1 after surgery. Data are means ± SD from n = 4 mice/group. *P<0.05 versus control (WT).(F) Ischemic reperfusion was suppressed by CXCR4 antibody treatment in WT, but not in TK-/- on day 28 after surgical treatment. Data are means ± SD from n = 6 mice/group. *P<0.05 versus control (IgG).
Mentions: The growth of granulation tissue and the generation of new microvessels through angiogenesis are stimulated by angiogenesis-stimulating factors, VEGF-A and SDF-1. VEGF and SDF-1 mobilize BM-derived VEGFR1+ to promote tumor growth [13,14]. The mRNA level of VEGFA (Fig 5A) and the plasma level of VEGF in both WT and TK-/- were significantly elevated on day 1 relative to day 0; however, there was no difference between the groups on day 1 (147.04 ± 25.2 pg/mL vs. 155.75 ± 38.06 pg/mL, respectively; P = 0.716, n = 5 per group, Fig 5B). By contrast, the mRNA level of SDF-1 (Fig 5C) and the plasma level of SDF-1 were significantly lower in TK-/- than in WT on day 3 (0.72 ± 0.12 ng/mL vs. 1.10 ± 0.15 ng/mL, respectively; P<0.05, n = 5 per group) and day 5 (0.90 ± 0.10 ng/mL vs. 1.39 ± 0.07 ng/mL, respectively; P<0.05, n = 5 per group, Fig 5D). Moreover, the expression of CXCR4, the specific ligand for SDF-1, was significantly suppressed in TK-/- (Fig 5E).

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