LRP1 promotes synthetic phenotype of pulmonary artery smooth muscle cells in pulmonary hypertension

Zucker, Marius M.; Wujak, Lukasz; Gungl, Anna; Didiášová, Miroslava; Kosanovic, Djuro; Petrović, A; Klepetko, Walter; Schermuly, Ralph T.; Kwapiszewska, Grażyna; Schaefer, Liliana; Wygrecka, Małgorzata

doi:10.1016/j.bbadis.2019.03.012

Cited by 25 publications

(16 citation statements)

References 43 publications

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“…It is feasible that LRP1 directly suppresses adult OPC proliferation. LRP1 is known to modulate the proliferation of other cell types (Boucher et al, 2007;Basford et al, 2009;Mao et al, 2016;Safina et al, 2016;Yang et al, 2018;Zucker et al, 2019), suppressing the hypoxia-induced proliferation of mouse and human retinal endothelial cells by regulating the activity of poly (ADP-ribose) polymerase-1 (PARP-1; Mao et al, 2016), and suppressing the proliferation of cultured mouse vascular smooth muscle cells by reducing PDGFRβ activity (Boucher et al, 2003;Basford et al, 2009). However, the inability of Lrp1 deletion to acutely influence OPC proliferation in vivo or directly influence OPC proliferation in vitro (Figure 7; Lin et al, 2017), may suggest that LRP1 affects OPC proliferation indirectly.…”

Section: Why Does Lrp1 Deletion Have a Delayed Effect On Opc Prolifermentioning

confidence: 99%

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain

Auderset

Pitman

Cullen

et al. 2020

Front. Cell Dev. Biol.

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Section: Why Does Lrp1 Deletion Have a Delayed Effect On Opc Prolifermentioning

confidence: 99%

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain

Auderset

Pitman

Cullen

et al. 2020

Front. Cell Dev. Biol.

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“…Additionally, we found some interactions uniquely from adipose endothelial cells (Figure 5B, in the red boxes) that might affect tumor growth. First, adipose endothelial cells expressed LAGLS9 and PDGFB binding to LRP1, which can enhance expression of collagen 1, 49 thus consolidating the connection between tumor cells and adipose endothelial cells. Second, adipose endothelial cells expressed EFNA1 binding with EPHA7 and EPHA4, both of which were reported to accelerate tumor growth 50‐52 .…”

Section: Resultsmentioning

confidence: 99%

“…and PDGFB binding to LRP1, which can enhance expression of collagen 1, 49 thus consolidating the connection between tumor cells and adipose endothelial cells. Second, adipose endothelial cells expressed EFNA1 binding with EPHA7 and EPHA4, both of which were reported to accelerate tumor growth.…”

Section: Heterogeneity Of Nk Cells In Gistmentioning

confidence: 99%

Single‐cell transcriptome analysis revealed the heterogeneity and microenvironment of gastrointestinal stromal tumors

et al. 2021

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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract. In this study, we performed single‐cell RNA sequencing (RNA‐seq) on intra‐ and peri‐tumor tissues from GIST patients with the aim of discovering the heterogeneity of tumor cells in GIST and their interactions with other cells. We found four predominating cell types in GIST tumor tissue, including T cells, macrophages, tumor cells, and NK cells. Tumor cells could be clustered into two groups: one was highly proliferating and associated with high risk of metastasis, the other seemed “resting” and associated with low risk. Their clinical relevance and prognostic values were confirmed by RNA‐seq of 65 GIST samples. T cells were the largest cell type in our single‐cell data. Two groups of CD8+ effector memory (EM) cells were in the highest clonal expansion and performed the highest cytotoxicity but were also the most exhausted among all T cells. A group of macrophages were found polarized to possess both M1 and M2 signatures, and increased along with tumor progression. Cell‐to‐cell interaction analysis revealed that adipose endothelial cells had high interactions with tumor cells to facilitate their progression. Macrophages were at the center of the tumor microenvironment, recruiting immune cells to the tumor site and having most interactions with both tumor and nontumor cells. In conclusion, we obtained an overview of the GIST microenvironment and revealed the heterogeneity of each cell type and their relevance to risk classifications, which provided a novel theoretical basis for learning and curing GISTs.

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“…In IPAH lung, based on the MSX1 protein localization in remodeled pulmonary arteries, we believe that MSX1 could potentially be localized in the dedifferentiated PASMCs. This is because, according to the current concept of PH pathogenesis, PASMCs can undergo a phenotypic switch from a contractile (differentiated) to a synthetic/proliferative (dedifferentiated) state that drives medial thickening and vascular remodeling in PH [ 47 , 48 ]. It is therefore possible that, in PAH, ectopic MSX1 expression could prompt dedifferentiation of PASMCs and influence remodeling of pulmonary arteries.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Msx1 in Mouse Lung Leads to Loss of Pulmonary Vessels Following Vascular Hypoxic Injury

West¹,

Rathinasabapathy²,

Chen³

et al. 2021

Cells

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Pulmonary arterial hypertension (PAH) is a progressive lung disease caused by thickening of the pulmonary arterial wall and luminal obliteration of the small peripheral arteries leading to increase in vascular resistance which elevates pulmonary artery pressure that eventually causes right heart failure and death. We have previously shown that transcription factor Msx1 (mainly expressed during embryogenesis) is strongly upregulated in transformed lymphocytes obtained from PAH patients, especially IPAH. Under pathological conditions, Msx1 overexpression can cause cell dedifferentiation or cell apoptosis. We hypothesized that Msx1 overexpression contributes to loss of small pulmonary vessels in PAH. In IPAH lung, MSX1 protein localization was strikingly increased in muscularized remodeled pulmonary vessels, whereas it was undetectable in control pulmonary arteries. We developed a transgenic mouse model overexpressing MSX1 (MSX1OE) by about 4-fold and exposed these mice to normoxic, sugen hypoxic (3 weeks) or hyperoxic (100% 02 for 3 weeks) conditions. Under normoxic conditions, compared to controls, MSX1OE mice demonstrated a 30-fold and 2-fold increase in lung Msx1 mRNA and protein expression, respectively. There was a significant retinal capillary dropout (p < 0.01) in MSX1OE mice, which was increased further (p < 0.03) with sugen hypoxia. At baseline, the number of pulmonary vessels in MSX1OE mice was similar to controls. In sugen-hypoxia-treated MSX1OE mice, the number of small (0–25 uM) and medium (25–50 uM) size muscularized vessels increased approximately 2-fold (p < 0.01) compared to baseline controls; however, they were strikingly lower (p < 0.001) in number than in sugen-hypoxia-treated control mice. In MSX1OE mouse lung, 104 genes were upregulated and 67 genes were downregulated compared to controls. Similarly, in PVECs, 156 genes were upregulated and 320 genes were downregulated from siRNA to MSX1OE, and in PVSMCs, 65 genes were upregulated and 321 genes were downregulated from siRNA to MSX1OE (with control in the middle). Many of the statistically significant GO groups associated with MSX1 expression in lung, PVECs, and PVSMCs were similar, and were involved in cell cycle, cytoskeletal and macromolecule organization, and programmed cell death. Overexpression of MSX1 suppresses many cell-cycle-related genes in PVSMCs but induces them in PVECs. In conclusion, overexpression of Msx1 leads to loss of pulmonary vessels, which is exacerbated by sugen hypoxia, and functional consequences of Msx1 overexpression are cell-dependent.

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LRP1 promotes synthetic phenotype of pulmonary artery smooth muscle cells in pulmonary hypertension

Cited by 25 publications

References 43 publications

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain

Single‐cell transcriptome analysis revealed the heterogeneity and microenvironment of gastrointestinal stromal tumors

Overexpression of Msx1 in Mouse Lung Leads to Loss of Pulmonary Vessels Following Vascular Hypoxic Injury

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