scholarly journals Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease

2021 ◽  
Author(s):  
David Rohde ◽  
Katrien Vandoorne ◽  
I-Hsiu Lee ◽  
Jana Grune ◽  
Shuang Zhang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Bone Marrow ◽  
Endothelial Dysfunction ◽  
Myeloid Cell ◽  
Vegf Receptor ◽  
Bone Marrow Niche ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Endothelial Growth Factor ◽  
Inflammatory Leukocytes

AbstractAbnormal hematopoiesis advances cardiovascular disease by generating excess inflammatory leukocytes that attack the arteries and the heart. The bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, but whether cardiovascular disease affects the hematopoietic organ’s microvasculature is unknown. Here we show that hypertension, atherosclerosis and myocardial infarction (MI) instigate endothelial dysfunction, leakage, vascular fibrosis and angiogenesis in the bone marrow, altogether leading to overproduction of inflammatory myeloid cells and systemic leukocytosis. Limiting angiogenesis with endothelial deletion of Vegfr2 (encoding vascular endothelial growth factor (VEGF) receptor 2) curbed emergency hematopoiesis after MI. We noted that bone marrow endothelial cells assumed inflammatory transcriptional phenotypes in all examined stages of cardiovascular disease. Endothelial deletion of Il6 or Vcan (encoding versican), genes shown to be highly expressed in mice with atherosclerosis or MI, reduced hematopoiesis and systemic myeloid cell numbers in these conditions. Our findings establish that cardiovascular disease remodels the vascular bone marrow niche, stimulating hematopoiesis and production of inflammatory leukocytes.

The Production of Vascular Endothelial Growth Factor Is Decreased in Acute Myelogenous Leukemia Cases That Are Treated with Chemotherapeutic Agents and Show the Prolonged Bone Marrow Suppression.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4313-4313
Author(s):  
Haruko Tashiro ◽  
Mitsuho Noguchi ◽  
Ryosuke Shirasaki ◽  
Kazuo Kawasugi ◽  
Naoki Shirafuji
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Bone Marrow Cells ◽  
Bone Marrow Suppression ◽  
Myelogenous Leukemia ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Acute Myelogenous ◽  
Endothelial Growth Factor ◽  
Marrow Cells

Abstract Objective: There have been reported that the levels of serum vascular endothelial growth factor (VEGF) were decreased in aplastic anemia cases. We investigated VEGF system after chemotherapy to acute myelogenous leukemia (AML) cases, and determined whether VEGF system influenced the prolonged bone marrow suppression in these cases. Materials and Methods: Sera and bone marrow cells were prepared from 30 AML cases including 10 cases of AML (M3) at the onset of the disease, after chemotherapy, and the recovery periods, and the concentration of VEGF in sera of the patients and in the conditioned media obtained from bone marrow-cell cultures was measured with ELISA kit (Quantikine; R&D Systems). The expression of VEGF, VEGF receptor type-1 and VEGF receptor type-2 was analyzed with RT-PCR. The biological effect of VEGF on the bone marrow cells which showed the prolonged suppression after chemotherapy was assayed with colony-formation with or without any cytokines. Result and Discussion: As was reported previously, VEGF levels were significantly increased in M3 cases. In other types of AML cases the levels of VEGF production varied. When patients were given chemotherapy and the bone marrow suppression was prolonged, the production levels of VEGF were significantly diminished less than that observed in AML cases with normal bone marrow recovery. In M3 cases that were treated with all-trans retinoic acid and the prolonged bone marrow-suppression was observed, VEGF production was also suppressed. The expression of VEGFR-1 and -2 was observed in bone marrow cells from prolonged bone marrow suppression cases. In these cases, when bone marrow cells were cultured with VEGF, synergistic effects with G-CSF and EPO were observed with colony-formation assay. These observations indicate that VEGF works on the important role for the hematopoietic recovery after chemotherapy in AML cases.

scholarly journals Vascular Endothelial Growth Factor and Angiopoietin-1 Stimulate Postnatal Hematopoiesis by Recruitment of Vasculogenic and Hematopoietic Stem Cells

2001 ◽  
Vol 193 (9) ◽  
pp. 1005-1014 ◽  
Author(s):  
Koichi Hattori ◽  
Sergio Dias ◽  
Beate Heissig ◽  
Neil R. Hackett ◽  
David Lyden ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Hematopoietic Stem Cells ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Neutralizing Monoclonal Antibody ◽  
Endothelial Growth Factor ◽  
Angiopoietin 1

Tyrosine kinase receptors for angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) are expressed not only by endothelial cells but also by subsets of hematopoietic stem cells (HSCs). To further define their role in the regulation of postnatal hematopoiesis and vasculogenesis, VEGF and Ang-1 plasma levels were elevated by injecting recombinant protein or adenoviral vectors expressing soluble VEGF165, matrix-bound VEGF189, or Ang-1 into mice. VEGF165, but not VEGF189, induced a rapid mobilization of HSCs and VEGF receptor (VEGFR)2+ circulating endothelial precursor cells (CEPs). In contrast, Ang-1 induced delayed mobilization of CEPs and HSCs. Combined sustained elevation of Ang-1 and VEGF165 was associated with an induction of hematopoiesis and increased marrow cellularity followed by proliferation of capillaries and expansion of sinusoidal space. Concomitant to this vascular remodeling, there was a transient depletion of hematopoietic activity in the marrow, which was compensated by an increase in mobilization and recruitment of HSCs and CEPs to the spleen resulting in splenomegaly. Neutralizing monoclonal antibody to VEGFR2 completely inhibited VEGF165, but not Ang-1–induced mobilization and splenomegaly. These data suggest that temporal and regional activation of VEGF/VEGFR2 and Ang-1/Tie-2 signaling pathways are critical for mobilization and recruitment of HSCs and CEPs and may play a role in the physiology of postnatal angiogenesis and hematopoiesis.

Induction of nitric oxide by erythropoietin is mediated by the β common receptor and requires interaction with VEGF receptor 2

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 896-905 ◽  
Author(s):  
Larysa Sautina ◽  
Yuri Sautin ◽  
Elaine Beem ◽  
Zhuo Zhou ◽  
Anna Schuler ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Common Receptor ◽  
The Common ◽  
Β Receptor ◽  
And Performance ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) have profound effects on the endothelium and endothelial progenitor cells (EPCs), which originate from the bone marrow and differentiate into endothelial cells. Both EPO and VEGF have demonstrated an ability to increase the number and performance properties of EPCs. EPC behavior is highly dependent on nitric oxide (NO), and both VEGF and EPO can stimulate intracellular NO. EPO can bind to the homodimeric EPO receptor (EPO-R) and the heterodimeric receptor, EPO-R and the common β receptor (βC-R). Although VEGF has several receptors, VEGF-R2 appears most critical to EPC function. We demonstrate that EPO induction of NO is dependent on the βC-R and VEGF-R2, that VEGF induction of NO is dependent on the expression of the βC-R, and that the βC-R and VEGF-R2 interact. This is the first definitive functional and structural evidence of an interaction between the 2 receptors and has implications for the side effects of EPO.

VEGF resistance as a molecular basis to explain the angiogenesis paradox in diabetes mellitus

2009 ◽  
Vol 37 (6) ◽  
pp. 1167-1170 ◽  
Author(s):  
Johannes Waltenberger
Keyword(s):  
Diabetes Mellitus ◽  
Signal Transduction ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Molecular Basis ◽  
Protein Tyrosine Phosphatases ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Intracellular Pathways ◽  
Endothelial Growth Factor

The action of VEGF (vascular endothelial growth factor) is essential to maintain proper endothelial and vascular function. VEGF stimulates virtually all aspects of endothelial function, namely proliferation, migration, permeability and nitric oxide production and release. In addition, the action of VEGF makes the endothelium anti-apoptotic. In turn, the inhibition of VEGF action is associated with endothelial dysfunction. Likewise, endothelial dysfunction can be found in the presence of several cardiovascular risk factors, including diabetes mellitus, hypercholesterolaemia and smoking. As circulating monocytes express functionally active VEGFR-1 (VEGF receptor 1) on their surface, monocytes and the related VEGFR-1-mediated signal transduction cascades have come into focus. The function of monocytes is negatively affected by diabetes mellitus, resulting in monocyte dysfunction. More specifically, a VEGF-related signal transduction defect can be detected in monocytes isolated from diabetic individuals. This reduced monocyte response to VEGF, demonstrated by a reduced chemotactic response, can be regarded as VEGF resistance. It is based on the pre-activation of certain intracellular pathways secondary to the diabetes mellitus-related RAGE (receptor for advanced glycation end-products) activation, ROS (reactive oxygen species) activation and inhibition of PTPs (protein tyrosine phosphatases). This unspecific pre-activation of intracellular pathways represents the molecular basis of VEGF resistance in diabetes mellitus.

scholarly journals Vascular Endothelial Growth Factor A (VEGF-A) Is Involved in Guidance of VEGF Receptor-Positive Cells to the Anterior Portion of Early Embryos

2005 ◽  
Vol 25 (1) ◽  
pp. 355-363 ◽  
Author(s):  
Sachie Hiratsuka ◽  
Yuki Kataoka ◽  
Kazuki Nakao ◽  
Kenji Nakamura ◽  
Shunichi Morikawa ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Anterior Portion ◽  
Whole Embryo Culture ◽  
Posterior Portion ◽  
Hematopoietic Stem ◽  
Endothelial Growth Factor

ABSTRACT The hemangioblast in the mesoderm gives rise to both angioblasts and hematopoietic stem cells. The movement of hemangioblast precursor cells in the fetal trunk is a critical event in early embryogenesis. Vascular endothelial growth factor (VEGF) signaling is likely involved in this migration given the partial disturbance of VEGF receptor (VEGFR)-positive cell accumulation and migration in VEGFR2 null mice or mice with a truncated VEGFR1. However, it is not clear how the VEGF system regulates this migration or its direction. We show here that the expression of VEGF-A is dominant in the anterior portion of the embryo, whereas VEGFR1 and VEGFR2 are expressed in the posterior portion of the embryo. An inhibitor of VEGFR kinase blocked the migration of VEGFR-positive cells in a whole-embryo culture system. In addition, VEGFR-positive cells migrated toward a VEGFR1- or VEGFR2-specific ligand in vitro. Furthermore, VEGFR-positive cells derived from wild-type or VEGFR2+/− mice moved rapidly anteriorly, whereas cells derived from VEGFR2+/− mice carrying a truncated VEGFR1 [VEGFR1(TM-TK)−/−] migrated little when injected into wild-type mice. These results suggest that the VEGF-A protein concentrated in the anterior region plays an important role in the guidance of VEGFR-positive cells from the posterior portion to the head region by interacting with VEGFR in the mouse embryo.

scholarly journals Endothelial dysfunction in patients with lymphoproliferative disorders and its changes in the course of polychemotherapy

2020 ◽  
Vol 9 (3) ◽  
Author(s):  
Igor L. Davydkin ◽  
Tatyana P. Kuzmina ◽  
Ksenia V. Naumova ◽  
Rais K. Khayretdinov ◽  
Olesya E. Danilova ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Lymphoproliferative Disorders ◽  
Vascular Endothelial ◽  
Cardiovascular Toxicity ◽  
Cardiovascular Damage ◽  
Before And After ◽  
Chemotherapeutic Treatment ◽  
Endothelial Growth Factor

The article is dedicated to contemporary views on the change of endothelial function in the patients with lymphoproliferative disorders prior to, and in the process of, chemotherapeutic treatment. Considering that possibilities of standard examination do not always help identifying subclinical endothelial dysfunction, it is necessary to use specific methods, in particular, to determine the levels of endothelin-1 and vascular endothelial growth factor to monitor endothelial function. The objective of this review is to identify problems and prospects for recognizing early subclinical changes of endothelial function in the patients with lymphoproliferative disorders before and after chemotherapy. Assessing presence and severity of endothelial dysfunction may be useful for determining subclinical stages of cardiovascular damage, stratifying the risk of the patients with confirmed cardiovascular disease, and reducing the likelihood of cardio- and endotheliotoxic effects in patients long after chemotherapy. That is why early detection and immediate therapy of cardiovascular toxicity is currently the most important task in the patients with lymphoproliferative disorders, receiving chemotherapy.

Leukemia-Derived Fibroblast Cells Produce Vascular Endothelial Growth Factor Significantly in Chronic Myelogenous Leukemia Cases.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4544-4544
Author(s):  
Ryosuke Shirasaki ◽  
Haruko Tashiro ◽  
Mitsuho Noguchi ◽  
Kazuo Kawasugi ◽  
Naoki Shirafuji
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Mononuclear Cells ◽  
Bone Marrow Cells ◽  
Myelogenous Leukemia ◽  
Stromal Fibroblast ◽  
Vegf Receptor ◽  
Fibroblast Cells ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Abstract Objective: We reported recently that myofibroblast cells in bone marrow cells of chronic myelogenous leukemia (CML)-patients were partly derived from CML clone, which was identified after long-term bone marrow cell-cultures. The generated BCR-ABL-positive fibroblast cells produced various kinds of cytokines more than that observed in the normal clone-derived fibroblast cells. Among these cytokines, we focus on vascular endothelial growth factor (VEGF)-system in this report. Materials and Methods: Bone marrow cells were collected from chronic myelogenous leukemia cases (20 of chronic phase (CP), 3 of accelerated phase (AP), 8 of blast crisis phase (BC)), which were separated with gravity sedimentation. Obtained non-adherent mononuclear cells were cultured in DMEM with 10% FCS in the humidified 5% CO2 incubator. When cells showed morphological changes into fibroblastoid cells, cells were treated with trypsin and further cultured. The obtained stromal fibroblast cells were sub-cloned into culturing in 96 well plates, and from which RNAs were extracted. cDNAs were synthesized, and RT-PCR was performed to identify BCR-ABL fusion product. The selected clones were further analyzed on DNA levels with FISH to identify BCR-ABL. The concentration of VEGF in the patients’ sera and in the conditioned media of non-adherent mononuclear cells, of fibroblast cells derived from normal clone and of fibroblast cells with BCR-ABL was measured with ELISA kit (R&D Systems). The expression of VEGF, VEGF receptor type-1 and VEGF receptor type-2 was also compared at RNA levels. The effect of anti-VEGF antibody to the culturing CML cells was determined using 3H-incorporation assay system. Results and Discussion: The levels of VEGF in sera from CML patients were elevated significantly. However, in patients with CP the expression of VEGF was not observed in non-adherent mononuclear cells. In contrast, VEGF production was observed in non-adherent mononuclear cells from the patients with AP and BC. Stromal fibroblasts produced VEGF in CP, AP and BC, in which BCR-ABL-positive fibroblast cells produced at the significant levels. The expression of VEGFR-1 and -2 was detected in non-adherent mononuclear cells from CP, AP and BC. When non-adherent mononuclear cells from CML patients were cultured onto the stromal fibroblast cells, significant additive effects were observed with 3H-thymidine incorporation assays. And when anti VEGF antibody was added to the cultures, the proliferation activity was significantly decreased. These observations indicate that in CML cases, especially in CP, VEGF plays an important role for the cellular proliferation with paracrine system.

scholarly journals Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1α

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4258-4263 ◽  
Author(s):  
Keita Kirito ◽  
Norma Fox ◽  
Norio Komatsu ◽  
Kenneth Kaushansky
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Stem Cell ◽  
Growth Factor ◽  
Hematopoietic Cells ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Hematopoietic Stem ◽  
Endothelial Growth Factor ◽  
Marrow Cells

Abstract Thrombopoietin (TPO), the primary regulator of thrombopoiesis, is also an important, nonredundant mediator of hematopoietic stem cell (HSC) development. For example, following transplantation, HSC expansion is approximately 15-fold more robust in normal than in Tpo-/- mice. Vascular endothelial growth factor (VEGF) also plays an important role in HSC development, where it acts in an intracellular autocrine fashion to promote cell survival. Thus, we tested the hypothesis that TPO affects the autocrine production of VEGF to account for its favorable effects on HSCs. We found that VEGF transcripts are reduced in purified sca-1+/c-kit+/Gr-1- marrow cells derived from Tpo-/- mice and that TPO induces VEGF transcripts in these primitive hematopoietic cells. Additional studies determined that TPO induces VEGF expression by increasing the level of its primary transcription factor, hypoxia-inducible factor 1α (HIF-1α), by enhancing its protein stability. Moreover, VEGF expression is important for the TPO effect on primitive hematopoietic cells because blockade of the VEGF receptor with a specific inhibitor substantially blunts TPO-induced growth of single sca-1+/c-kit+/Gr-1- marrow cells in serum-free cultures. Along with previous findings that TPO affects Hox transcription factors that regulate HSC proliferation, these data contribute to our growing understanding of the mechanisms by which a hormone can influence stem cell development.

Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 1849-1856 ◽  
Author(s):  
Masato Murakami ◽  
Shinobu Iwai ◽  
Sachie Hiratsuka ◽  
Mai Yamauchi ◽  
Kazuhide Nakamura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Bone Destruction ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Human T Cell ◽  
Endothelial Growth Factor

AbstractVascular endothelial growth factor (VEGF) and VEGF receptor-1 (VEGFR-1/Flt-1) were shown to be involved in pathological angiogenesis, particularly rheumatoid arthritis (RA). However, the molecular basis of their actions is not fully understood. Here we report that in a murine model of RA, deletion of the tyrosine kinase (TK) domain of VEGFR-1 decreased the incidence and clinical symptoms of RA. Pathological symptoms, such as synovial hyperplasia, inflammatory infiltrates, pannus formation, and cartilage/bone destruction, became milder in Vegfr-1 tk–/– mice compared with wild-type (Wt) mice in the human T-cell leukemia virus-1 (HTLV-1) pX–induced chronic models. VEGFR-1 TK-deficient bone marrow cells showed a suppression of multilineage colony formation. Furthermore, macrophages induced to differentiate in vitro showed a decrease in immunologic reactions such as phagocytosis and the secretion of interleukin-6 (IL-6) and VEGF-A. Treatment of this RA model with a small molecule inhibitor for VEGFR TK, KRN951, also attenuated the arthritis. These results indicate that the VEGFR-1 TK signaling modulates the proliferation of bone marrow hematopoietic cells and immunity of monocytes/macrophages and promotes chronic inflammation, which may be a new target in the treatment of RA.

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