High expression of CXCR4 and stem cell markers in a monocrotaline and chronic hypoxia‑induced rat model of pulmonary arterial hypertension

Zhang, Tingting; Kawaguchi, Nanako; Hayama, Emiko; Furutani, Yoshiyuki; Nakanishi, Toshio

doi:10.3892/etm.2018.6027

Cited by 17 publications

(21 citation statements)

References 30 publications

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“…To figure out mechanisms leading to the disturbed accumulation of MDSC in the pregnant uterus of myeloid HIF-KO mice we analyzed expression of chemokine receptors and integrins on MDSC. Although upregulation via HIF-1α signaling pathways has been described for many surface receptors including CXCR1 and CXCR2 (33), CXCR4 (34), and IL-4Rα (35), we found no differences in their expression on MDSC from WT and myeloid HIF-KO mice. ITGB2 and ITGA4 were found to be upregulated in HIF-KO MDSC confirming other studies that showed negative regulation of ITGA4 by HIF-1α (36) but not explaining the reduced MDSC-accumulation in the uterus.…”

Section: Resultscontrasting

confidence: 80%

HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice

et al. 2019

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Abortions are the most important reason for unintentional childlessness. During pregnancy, maternal immune cells are in close contact to cells of the semi-allogeneic fetus. Dysregulation of the maternal immune system leading to defective adaptation to pregnancy often plays a role in pathogenesis of abortions. Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress functions of other immune cells, especially T-cells, thereby negatively affecting diseases such as cancer, sepsis or trauma. They seem, however, also necessary for maintenance of maternal-fetal tolerance. Mechanisms regulating MDSC expansion and function during pregnancy are only incompletely understood. In tumor environment, hypoxia is crucial for MDSC accumulation and activation. Hypoxia is also important for early placenta and embryo development. Effects of hypoxia are mediated through hypoxia-inducible factor 1α (HIF-1α). In the present study we aimed to examine the role of HIF-1α in myeloid cells for MDSC accumulation and MDSC function during pregnancy and for pregnancy outcome. We therefore used a mouse model with targeted deletion of HIF-1α in myeloid cells (myeloid HIF-KO) and analyzed blood, spleens and uteri of pregnant mice at gestational day E 10.5 in comparison to non-pregnant animals and wildtype (WT) animals. Further we analyzed pregnancy success by determining rates of failed implantation and abortion in WT and myeloid HIF-KO animals. We found that myeloid HIF-KO in mice led to an abrogated MDSC accumulation in the pregnant uterus and to impaired suppressive activity of MDSC. While expression of chemokine receptors and integrins on MDSC was not affected by HIF-1α, myeloid HIF-KO led to increased apoptosis rates of MDSC in the uterus. Myeloid-HIF-KO resulted in increased proportions of non-pregnant animals after positive vaginal plug and increased abortion rates, suggesting that activation of HIF-1α dependent pathways in MDSC are important for maintenance of pregnancy.

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Section: Resultscontrasting

confidence: 80%

HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice

et al. 2019

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“…Increased expression of CXCR4, a receptor for the chemokine stromal cell derived factor 1 (SDF1), has been reported in the lungs of patients with IPAH, HPAH and PAH associated with congenital heart defect [48]. Increased Cxcr4 was also reported in Sugen + hypoxia and monocrotalin + hypoxia rodent models of PH [49]. Inhibition of Cxcr4 moderately attenuated pulmonary vascular remodeling in the Sugen + hypoxia model [50] while overexpression of Cxcr4 participates in the repair of tissue injury [51].…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Mathew

Huang

Iacobaş

et al. 2019

Preprint

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Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), lung histology and transcriptomes of six weeks old male rats with PH induced by: 1) hypoxia (HO), 2) administration of monocrotaline (CM) or 3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations and also neointimal lesions and obliteration of lumen in small arteries. We found that the PH increased the expression of caveolin1, matrix metallopeptidase 2 and numerous inflammatory and cell proliferation genes. The cell-cycle, vascular smooth muscle contraction and the oxidative phosphorylation pathways, as well as their interplay were largely perturbed. Our results also suggest that the up-regulated Rhoa (ras homolog family member A) mediates its action through expression coordination with several ATPases. The upregulation of antioxidant genes and the extensive mitochondrial damage observed especially in HM group, indicate metabolic shift towards aerobic glycolysis.

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“…Soluble factors such as CXCL12 can promote the proliferation of pulmonary artery smooth muscle cells, which can result in PAH [76]. We have demonstrated that, although there was no significant difference in the SDF-1 expression levels between the control group and PAH using a rat model, there were significant differences in the CXCR4 expression levels between these two groups, suggesting that CXCR4 signaling is also involved in PAH development [77]. Interestingly, smooth muscle cell (SMC)-specific phosphatase and tensin homolog (PTEN) deficient mice display an aorta structure similar to PAH, and SDF-1/CXCR4 is upregulated.…”

Section: Cxcr4 Involvement In Abnormal Pathological Developmentmentioning

confidence: 99%

Involvement of CXCR4 in Normal and Abnormal Development

Kawaguchi

Zhang

Nakanishi

2019

Cells

Self Cite

131

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CXC motif chemokine receptor type 4 (CXCR4) is associated with normal and abnormal development, including oncogenesis. The ligand of CXCR4 is stromal cell-derived factor (SDF), also known as CXC motif ligand (CXCL) 12. Through the SDF-1/CXCR4 axis, both homing and migration of hematopoietic (stem) cells are regulated through niches in the bone marrow. Outside of the bone marrow, however, SDF-1 can recruit CXCR4-positive cells from the bone marrow. SDF/CXCR4 has been implicated in the maintenance and/or differentiation of stemness, and tissue-derived stem cells can be associated with SDF-1 and CXCR4 activity. CXCR4 plays a role in multiple pathways involved in carcinogenesis and other pathologies. Here, we summarize reports detailing the functions of CXCR4. We address the molecular signature of CXCR4 and how this molecule and cells expressing it are involved in either normal (maintaining stemness or inducing differentiation) or abnormal (developing cancer and other pathologies) events. As a constituent of stem cells, the SDF-1/CXCR4 axis influences downstream signal transduction and the cell microenvironment.

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High expression of CXCR4 and stem cell markers in a monocrotaline and chronic hypoxia‑induced rat model of pulmonary arterial hypertension

Cited by 17 publications

References 30 publications

HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice

HIF-1α-Deficiency in Myeloid Cells Leads to a Disturbed Accumulation of Myeloid Derived Suppressor Cells (MDSC) During Pregnancy and to an Increased Abortion Rate in Mice

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Involvement of CXCR4 in Normal and Abnormal Development

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