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Epithelial Vegfa Specifies a Distinct Endothelial Population in the Mouse Lung.

ABSTRACT: The lung microvasculature is essential for gas exchange and commonly considered homogeneous. We show that VEGFA from the epithelium is required for a distinct endothelial cell (EC) population in the mouse lung. Vegfa is predominantly expressed by alveolar type 1 (AT1) cells and locally required to specify a subset of ECs. Single-cell RNA sequencing (scRNA-seq) reveals that ?15% of lung ECs are transcriptionally distinct-marked by Carbonic anhydrase 4 (Car4)-and arise from bulk ECs, as suggested by trajectory analysis. Car4 ECs have extensive cellular projections and are separated from AT1 cells by a limited basement membrane without intervening pericytes. Car4 ECs are specifically lost upon epithelial Vegfa deletion; without Car4 ECs, the alveolar space is aberrantly enlarged despite the normal appearance of myofibroblasts. Lung Car4 ECs and retina tip ECs have common and distinct features. These findings support a signaling role of AT1 cells and shed light on alveologenesis.

SUBMITTER: Vila Ellis L

PROVIDER: S-EPMC7170573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (ANGPT2) are key mediators in angiogenesis. The expression and clinical significance of VEGFA and ANGPT2 have been investigated in lung cancer, but the results are controversial. The specific roles of VEGFA and ANGPT2 in adenocarcinoma (ADC) and squamous cell carcinoma (SQC) are still not fully understood. To characterize it, we conducted the current study. Materials and Methods: The relationships between clinic-pathological characteristics and the protein expressions of VEGFA and ANGPT2 were analyzed on tissue microarrays by immunohistochemistry (IHC) staining. Then public databases were used to evaluate the association of VEGFA and ANGPT2 mRNA expressions with clinic-pathological parameters and prognosis. Cobalt chloride (CoCl2) was adopted to mimic a hypoxic microenvironment and western blot was used to detect the expression of hypoxia inducible factor-1? (HIF-1?), VEGFA and ANGPT2 in lung cancer cell lines. Results: IHC staining revealed that the expressions of VEGFA and ANGPT2 were enriched in lung cancer tissues compared with normal tissues. Additionally, both VEGFA and ANGPT2 protein levels were significantly associated with the tumor size and lymph node metastasis only in ADC, not SQC. More importantly, increased VEGFA and ANGPT2 protein levels were negatively correlated with overall survival (OS) of ADC individuals. Meta-analyses of 22 gene expression omnibus (GEO) databases of lung cancer implicated that patients with higher VEGFA and ANGPT2 mRNA expressions tended to have advanced stage in ADC rather than SQC. Kaplan-Meier plot analyses further verified that high levels of VEGFA and ANGPT2 mRNA were associated with poor survival only in ADC. Moreover, the combination of VEGFA and ANGPT2 could more precisely predict prognosis in ADC. In hypoxia-mimicking conditions, induced expression of HIF-1? unregulated VEGFA and ANGPT2 proteins abundance. Conclusion: Our results showed hypoxia upregulated the protein levels of VEGFA and ANGPT2 in lung cancer cell lines, and the roles of VEGFA and ANGPT2 were distinct in ADC and SQC. Combined detections of VEGFA and ANGPT2 may be valuable prognostic biomarkers for ADC and double block of VEGFA and ANGPT2 may improve therapeutic outcome.

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Epithelial Vegfa Specifies a Distinct Endothelial Population in the Mouse Lung.

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