Hypoxia-induced proliferation of tissue-resident endothelial progenitor cells in the lung

Nishimura, Rintaro; Nishiwaki, Tetsu; Kawasaki, Takeshi; Sekine, Ayumi; Suda, Rika; Urushibara, Takashi; Suzuki, Toshio; Takayanagi, Shinji; Terada, Jiro; Sakao, Seiichiro

doi:10.1152/ajplung.00243.2014

Cited by 24 publications

(17 citation statements)

References 45 publications

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“…The present study revealed that hypoxia induced EPC proliferation. Nishimura et al (23) reported that hypoxia induced the proliferation of tissue-resident EPCs in the lung. Furthermore, Sen et al (22) indicated that exposure to pro-inflammatory cytokines, including angiotensin II, endothelin-1 and tumor necrosis factor, may result in EC dysfunction and the downregulation of S100A1 expression by inducing miR-138 in a manner dependent on the stabilization of HIF-1α.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Zhou

Zeng

Xiong

2017

Experimental and Therapeutic Medicine

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Abstract. Endothelial progenitor cells (EPCs) participate in angiogenesis by differentiating into endothelial cells (ECs)and may be developed to treat ischemia/reperfusion injury. MicroRNAs (miRs) are a type of non-coding RNA that are 18-25 nucleotides in length and serve a role in angiogenesis. It has been demonstrated that miR-138 regulates hypoxia-induced EC dysfunction. However, to the best of our knowledge, the exact role of miR-138 in the regulation of hypoxia-induced EPCs has not previously been reported. In the present study, data collected from an MTT assay indicated that hypoxia treatment enhanced EPC proliferation, which was accompanied by an upregulation of hypoxia-inducible factor 1α (HIF-1α) expression. miR-138 overexpression inhibited hypoxia-induced EPC proliferation and induced cell cycle arrest at the G1 stage. A mechanistic investigation revealed that miR-138 negatively regulated HIF-1α protein levels but did not affect HIF-1α mRNA levels in EPCs. Moreover, results from a dual luciferase reporter assay demonstrated that HIF-1α was a direct target of miR-138 in EPCs. Furthermore, upregulation of miR-138 suppressed the hypoxia-induced upregulation of HIF-1α. Downstream factors of HIF-1α were also investigated and it was observed that the upregulation of miR-138 inhibited the hypoxia-induced upregulation of vascular endothelial growth factor, as well as the activity of mitogen-activated protein kinase and AKT signaling in EPCs. In summary, the present study suggested that miR-138 inhibits hypoxia-induced EPC proliferation, possibly by inhibiting HIF-1α-mediated signaling.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Zhou

Zeng

Xiong

2017

Experimental and Therapeutic Medicine

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“…Exposure to chronic hypoxia for 21 days resulted in occlusive pulmonary arteriopathy and increased RVSP. The role of hypoxia for promoting proliferation of endothelial precursor cells has been shown previously in the lung 44 . Our results support a concept that the aberrant ECs in PAH occlusive vascular lesions develop by clonal selection from endothelial-like stem cells 4 .…”

Section: Discussionmentioning

confidence: 56%

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Bhagwani

Farkas

Harmon

et al. 2020

Sci Rep

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one current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells (ecs) contribute to severe pulmonary arterial hypertension (pAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). The remodelled pulmonary arteries of PAH patients harboured CD117 + ecs. Rat lung CD117 + ecs underwent four generations of clonal expansion to enrich hyperproliferative ecs. The resulting clonally enriched ECs behaved like ECs, as measured by in vitro and in vivo angiogenesis assays. The same primitive ECs showed a limited ability for mesenchymal lineage differentiation. Endothelial differentiation and function were enhanced by blocking TGF-β signalling, promoting bone morphogenic protein (BMP) signalling. The transplantation of the EC clones caused arterio-occlusive PH in rats exposed to chronic hypoxia. these ec clones engrafted in the pulmonary arteries. Yet cessation of chronic hypoxia promoted lung cell apoptosis and resolution of vascular lesions. In conclusion, this is to the best of our knowledge, the first report that clonally enriched primitive ECs promote occlusive pulmonary arteriopathy and severe pH. these primitive ec clones further give rise to cells of endothelial and mesenchymal lineage as directed by BMP and TGF-β signaling. Pulmonary arterial hypertension (PAH) remains a devastating disease with dismal prognosis. The pulmonary arteries of PAH patients have lesions of varying severity including formation of neointima, which obstructs the normal blood flow, and complex multicellular plexiform lesions. A current concept suggests that dysregulated programmed cell death, or apoptosis of ECs causes unchecked proliferation of a subset of apoptosis-resistant ECs 1,2. The ECs retain a hyperproliferative and apoptosis-resistant phenotype even in culture 3. These abnormal ECs in the plexiform lesions of PAH patients may originate from primitive endothelial-like stem cells by clonal selection 4. This concept of primitive cells as source of aberrant ECs in PAH is supported by the findings of markers of primitive stem-like cells in the lung vascular lesions 5-7. Likewise, hyperproliferative pulmonary artery smooth muscle cells may also be derived from progenitor cells in PAH 8,9. During vascular development, primitive ECs

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“…The formation of EC colonies is a feature shared by both EPCs and EC-SP cells; however, we found that EC-SP cells are EC lineagecommitted cells, which do not originate from the bone marrow. In the lung vasculature, the existence of highly proliferative resident progenitor cells that possess an endothelial colony-forming cell (ECFC)-like phenotype has been reported (38,39). ECFCs were originally described in human peripheral and umbilical cord blood based on the timing of their emergence in culture (40).…”

Section: Discussionmentioning

confidence: 99%

Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance

et al. 2016

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Angiogenesis plays a crucial role in tumor growth, with an undisputed contribution of resident endothelial cells (EC) to new blood vessels in the tumor. Here, we report the definition of a small population of vascular-resident stem/progenitor-like EC that contributes predominantly to new blood vessel formation in the tumor. Although the surface markers of this population are similar to other ECs, those from the lung vasculature possess colony-forming ability in vitro and contribute to angiogenesis in vivo. These specific ECs actively proliferate in lung tumors, and the percentage of this population significantly increases in the tumor vasculature relative to normal lung tissue. Using genetic recombination and bone marrow transplant models, we show that these cells are phenotypically true ECs and do not originate from hematopoietic cells. After treatment of tumors with antiangiogenic drugs, these specific ECs selectively survived and remained in the tumor. Together, our results established that ECs in the peripheral vasculature are heterogeneous and that stem/progenitor-like ECs play an indispensable role in tumor angiogenesis as EC-supplying cells. The lack of susceptibility of these ECs to antiangiogenic drugs may account for resistance of the tumor to this drug type. Thus, inhibiting these ECs might provide a promising strategy to overcome antiangiogenic drug resistance.

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Hypoxia-induced proliferation of tissue-resident endothelial progenitor cells in the lung

Cited by 24 publications

References 45 publications

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance

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