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Endothelial CXCL12 regulates neovascularization during tissue repair and tumor progression

ABSTRACT: Tissue repair and tumor progression are linked by their reliance on the response to ischemia. Coordinated interplay between resident and circulating cells, governed by a myriad of factors, is critical for new blood vessel formation and tissue survival in both. The vascular endothelium exhibits paracrine activity and provides an interface for the recruitment of circulating cells, which in turn influence the neovascularization and extra-vascular tissue growth. CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor 1 [SDF-1]) has been implicated in tumor biology and neovascularization, but its specific role and mechanism of action remain poorly understood. We have previously demonstrated that CXCL12 expression is hypoxia responsive and occurs in vascular endothelium. Here we use a conditional CXCL12 knockout mouse to show that endothelial-specific deletion of CXCL12 (eKO) reduces the survival of ischemic tissue, which alters both tissue repair and tumor progression. The loss of vascular endothelial CXCL12 disrupts endothelial – fibroblast crosstalk necessary for stromal growth and vascularization. Using single-cell gene expression analysis in combination with a parabiosis model, eKO is found to impair the recruitment of a specific population of non-inflammatory circulating cells defined by genes regulating cell survival and neovascularization. These findings indicate an essential role of endothelial CXCL12 expression during the adult neovascular response in tissue injury and tumor progression, paving the way for future therapeutic interventions.

ORGANISM(S): Mus musculus

PROVIDER: GSE146529 | GEO | 2020/03/07

REPOSITORIES: GEO

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Project description:Chen2006 - Nitric Oxide Release from Endothelial Cells This model is described in the article: Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells. Chen K, Popel AS. Free Radic. Biol. Med. 2006 Aug; 41(4): 668-680 Abstract: Vascular endothelium expressing endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO), which has a number of important physiological functions in the microvasculature. The rate of NO production by the endothelium is a critical determinant of NO distribution in the vascular wall. We have analyzed the biochemical pathways of NO synthesis and formulated a model to estimate NO production by the microvascular endothelium under physiological conditions. The model quantifies the NO produced by eNOS based on the kinetics of NO synthesis and the availability of eNOS and its intracellular substrates. The predicted NO production from microvessels was in the range of 0.005-0.1 microM/s. This range of predicted values is in agreement with some experimental values but is much lower than other rates previously measured or estimated from experimental data with the help of mathematical modeling. Paradoxical discrepancies between the model predictions and previously reported results based on experimental measurements of NO concentration in the vicinity of the arteriolar wall suggest that NO can also be released through eNOS-independent mechanisms, such as catalysis by neuronal NOS (nNOS). We also used our model to test the sensitivity of NO production to substrate availability, eNOS concentration, and potential rate-limiting factors. The results indicated that the predicted low level of NO production can be attributed primarily to a low expression of eNOS in the microvascular endothelial cells. This model is hosted on BioModels Database and identified by: BIOMD0000000676. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:The vascular endothelium constitutes the inner lining of the blood vessel and is directly involved in the control of blood fluidity, vascular tone, platelet aggregation, regulation of immunity, inflammation, and angiogenesis. Malfunction and injuries of the endothelium can cause cardiovascular diseases, which are the leading causes of death globally. The impairment of the endothelium is a hallmark in other diseases as well such as sepsis, stroke, tumor growth, insulin resistance, venous thrombosis, and chronic kidney failure. Generation of effective sources to replace injured endothelial cells (ECs) could have significant clinical impact and somatic cell sources like peripheral or cord blood cannot credibly supply enough endothelial cell progenitors for multitude of treatments. Pluripotent stem cells are a promising source for a reliable EC supply that have the potential to repair, reconstruct, replace damaged cells, and revascularize ischemic areas in order to restore tissue function and treat vascular diseases. We have developed methods to differentiate induced pluripotent stem cells (iPSCs) efficiently and robustly across multiple iPSC lines into non-tissue-specific pan vascular ECs (iECs) with high purity. These iECs present with canonical endothelial cell markers and exhibit measures of endothelial cell functionality with uptake of acetylated low-density lipoprotein (Dil-Ac-LDL) and tube formation. Using proteomic analysis, we revealed the iECs are more proteomically similar to established umbilical vein ECs (HUVECs) than to iPSCs. Post-translational modifications (PTMs) were most shared between HUVECs and iECs, and potential targets for increasing the proteomic similarity of iECs to HUVECs were identified. PTM analysis can be used in the future to glean additional insights and generate novel hypotheses. Here we demonstrate an efficient robust method to differentiate iPSCs into functional ECs, and for the first time provide a comprehensive protein expression profile of iECs, which indicates their similarities with a widely used immortalized HUVECs, allowing for further mechanistic studies of EC development, signaling and metabolism for future regenerative applications.

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Endothelial CXCL12 regulates neovascularization during tissue repair and tumor progression

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