Vascular endothelial growth factor receptor 1 signaling facilitates gastric ulcer healing and angiogenesis through the upregulation of epidermal growth factor expression on VEGFR1+CXCR4+ cells recruited from bone marrow

Sato, Takehito; Aoki, Hideki; Yoshiya, Ikuto; Eshima, Koji; Minamino, Tsutomu; Ae, Takako; Katada, Chikatoshi; Ohno, Takashi; Hosono, Kanako; Suzuki, Tatsunori; Shibuya, Masabumi; Koizumi, Wasaburo; Murakami, Masataka

doi:10.1007/s00535-013-0869-z

Cited by 25 publications

(33 citation statements)

References 41 publications

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“…The present study also suggests that VEGFR1-expressing macrophages are derived from the BM, and that the recruitment of BM-derived VEGFR1- expressing macrophages to the injured livers after hepatic I/R is dependent of VEGFR1 signaling, which is consistent with our recent results in a model of murine gastric ulcer healing [18] and wound healing [13]. VEGFR1 signaling in BM cells are crucial for not only the recruitment of VEGFR1-macrophages, but also the mobilization of VEGFR1-macrophages into circulation (Figure 5D).…”

Section: Discussionsupporting

confidence: 93%

“…For the BM transplantation experiments, transgenic mice expressing green fluorescent protein (GFP) against a C57BL/6 background were used to confirm BM chimerism. VEGFR1 TK -/- mice and GFP+/+ mice were crossed to obtain GFP+VEGFR1 TK -/- mice [18].…”

Section: Methodsmentioning

confidence: 99%

“…Bone marrow (BM) transplantation was performed as previously described [18]. Briefly, donor BM cells from GFP+VEGFR1 TK -/- mice and their GFP+WT counterparts were harvested using the same method [18].…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, donor BM cells from GFP+VEGFR1 TK -/- mice and their GFP+WT counterparts were harvested using the same method [18]. Donor BM-derived mononuclear cells (2×10 6 cells/200 µL PBS) were injected into the tail vein of irradiated WT mice.…”

Section: Methodsmentioning

confidence: 99%

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VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

et al. 2014

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Liver repair after acute liver injury is characterized by hepatocyte proliferation, removal of necrotic tissue, and restoration of hepatocellular and hepatic microvascular architecture. Macrophage recruitment is essential for liver tissue repair and recovery from injury; however, the underlying mechanisms are unclear. Signaling through vascular endothelial growth factor receptor 1 (VEGFR1) is suggested to play a role in macrophage migration and angiogenesis. The aim of the present study was to examine the role of VEGFR1 in liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion (I/R). VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK-/- mice) and wild-type (WT) mice were subjected to hepatic warm I/R, and the processes of liver repair and sinusoidal reconstruction were examined. Compared with WT mice, VEGFR1 TK-/- mice exhibited delayed liver repair after hepatic I/R. VEGFR1-expressing macrophages recruited to the injured liver showed reduced expression of epidermal growth factor (EGF). VEGFR1 TK-/- mice also showed evidence of sustained sinusoidal functional and structural damage, and reduced expression of pro-angiogenic factors. Treatment of VEGFR1 TK-/- mice with EGF attenuated hepatoceullar and sinusoidal injury during hepatic I/R. VEGFR1 TK-/- bone marrow (BM) chimeric mice showed impaired liver repair and sinusoidal reconstruction, and reduced recruitment of VEGFR1-expressing macrophages to the injured liver. VEGFR1-macrophages recruited to the liver during hepatic I/R contribute to liver repair and sinusoidal reconstruction. VEGFR1 activation is a potential therapeutic strategy for promoting liver repair and sinusoidal restoration after acute liver injury.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

et al. 2014

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“…VEGFR1 expression is sustained through day ten, at which point the endothelial-like cells arrange in a distinct pattern to line vessel-like structures [51]. Gastric ulcers were induced in RAG2 mice, and gastric ulcer healing in VEGFR1 knockout mice resulted in decreased CD31 mRNA levels and decreased microvessel density compared to wildtype mice, indicating that VEGFR1 has an important role in cell migration and vessel formation in gastric ulcer healing [52]. Additionally, VEGFR1 expression on highly metastatic 3LL-LLC tumor cells induces MMP9 expression in premetastatic lung endothelial cells and macrophages.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Characterization of Cellular Membrane-Receptor Heterogeneity through Statistical and Computational Modeling

Weddell

Imoukhuede

2014

PLoS ONE

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Cell population heterogeneity can affect cellular response and is a major factor in drug resistance. However, there are few techniques available to represent and explore how heterogeneity is linked to population response. Recent high-throughput genomic, proteomic, and cellomic approaches offer opportunities for profiling heterogeneity on several scales. We have recently examined heterogeneity in vascular endothelial growth factor receptor (VEGFR) membrane localization in endothelial cells. We and others processed the heterogeneous data through ensemble averaging and integrated the data into computational models of anti-angiogenic drug effects in breast cancer. Here we show that additional modeling insight can be gained when cellular heterogeneity is considered. We present comprehensive statistical and computational methods for analyzing cellomic data sets and integrating them into deterministic models. We present a novel method for optimizing the fit of statistical distributions to heterogeneous data sets to preserve important data and exclude outliers. We compare methods of representing heterogeneous data and show methodology can affect model predictions up to 3.9-fold. We find that VEGF levels, a target for tuning angiogenesis, are more sensitive to VEGFR1 cell surface levels than VEGFR2; updating VEGFR1 levels in the tumor model gave a 64% change in free VEGF levels in the blood compartment, whereas updating VEGFR2 levels gave a 17% change. Furthermore, we find that subpopulations of tumor cells and tumor endothelial cells (tEC) expressing high levels of VEGFR (>35,000 VEGFR/cell) negate anti-VEGF treatments. We show that lowering the VEGFR membrane insertion rate for these subpopulations recovers the anti-angiogenic effect of anti-VEGF treatment, revealing new treatment targets for specific tumor cell subpopulations. This novel method of characterizing heterogeneous distributions shows for the first time how different representations of the same data set lead to different predictions of drug efficacy.

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Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1+ cells from bone marrow

et al. 2017

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Vascular endothelial growth factor (VEGF)-A facilitates wound healing. VEGF-A binds to VEGF receptor 1 (VEGFR1) and VEGFR2 and induces wound healing through the receptor's tyrosine kinase (TK) domain. During blood flow recovery and lung regeneration, expression of VEGFR1 is elevated. However, the precise mechanism of wound healing, especially granulation formation on VEGFR1, is not well understood. We hypothesized that VEGFR1-TK signaling induces wound healing by promoting granulation tissue formation. A surgical sponge implantation model was made by implanting a sponge disk into dorsal subcutaneous tissue of mice. Granulation formation was estimated from the weight of the sponge and the granulation area from the immunohistochemical analysis of collagen I. The expression of fibroblast markers was estimated from the expression of transforming growth factor-beta (TGF-β) and cellular fibroblast growth factor-2 (FGF-2) using real-time PCR (polymerase chain reaction) and from the immunohistochemical analysis of S100A4. VEGFR1 TK knockout (TK) mice exhibited suppressed granulation tissue formation compared to that in wild-type (WT) mice. Expression of FGF-2, TGF-β, and VEGF-A was significantly suppressed in VEGFR1 TK mice, and the accumulation of VEGFR1 cells in granulation tissue was reduced in VEGFR1 TK mice compared to that in WT mice. The numbers of VEGFR1 cells and S100A4 cells derived from bone marrow (BM) were higher in WT mice transplanted with green fluorescent protein (GFP) transgenic WT BM than in VEGFR1 TK mice transplanted with GFP transgenic VEGFR1 TK BM. These results indicated that VEGFR1-TK signaling induced the accumulation of BM-derived VEGFR1 cells expressing F4/80 and S100A4 and contributed to granulation formation around the surgically implanted sponge area in a mouse model.

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Vascular endothelial growth factor receptor 1 signaling facilitates gastric ulcer healing and angiogenesis through the upregulation of epidermal growth factor expression on VEGFR1+CXCR4+ cells recruited from bone marrow

Abstract: VEGFR1-mediated signaling plays a critical role in gastric ulcer healing and angiogenesis through enhanced EGF expression on VEGFR1(+)CXCR4(+) cells recruited from the bone marrow into ulcer granulation tissue.

Cited by 25 publications

References 41 publications

VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

Quantitative Characterization of Cellular Membrane-Receptor Heterogeneity through Statistical and Computational Modeling

Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1+ cells from bone marrow

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