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Kindlin-2 controls angiogenesis through modulating Notch1 signaling

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Abstract

Kindlin-2 is critical for development and homeostasis of key organs, including skeleton, liver, islet, etc., yet its role in modulating angiogenesis is unknown. Here, we report that sufficient KINDLIN-2 is extremely important for NOTCH-mediated physiological angiogenesis. The expression of KINDLIN-2 in HUVECs is significantly modulated by angiogenic factors such as vascular endothelial growth factor A or tumor necrosis factor α. A strong co-localization of CD31 and Kindlin-2 in tissue sections is demonstrated by immunofluorescence staining. Endothelial-cell-specific Kindlin-2 deletion embryos die on E10.5 due to hemorrhage caused by the impaired physiological angiogenesis. Experiments in vitro show that vascular endothelial growth factor A-induced multiple functions of endothelial cells, including migration, matrix proteolysis, morphogenesis and sprouting, are all strengthened by KINDLIN-2 overexpression and severely impaired in the absence of KINDLIN-2. Mechanistically, we demonstrate that KINDLIN-2 inhibits the release of Notch intracellular domain through binding to and maintaining the integrity of NOTCH1. The impaired angiogenesis and avascular retinas caused by KINDLIN-2 deficiency can be rescued by DAPT, an inhibitor of γ-secretase which releases the intracellular domain from NOTCH1. Moreover, we demonstrate that high glucose stimulated hyperactive angiogenesis by increasing KINDLIN-2 expression could be prevented by KINDLIN-2 knockdown, indicating Kindlin-2 as a potential therapeutic target in treatment of diabetic retinopathy. Our study for the first time demonstrates the significance of Kindlin-2 in determining Notch-mediated angiogenesis during development and highlights Kindlin-2 as the potential therapeutic target in angiogenic diseases, such as diabetic retinopathy.

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Data availability

All data of this study are available within the article or the supplementary materials. All data are available from the corresponding authors upon reasonable request.

Abbreviations

VEGFA:

Vascular endothelial growth factor A

VEGFR2:

Vascular endothelial growth factor receptor 2

NICD:

Notch intracellular domain

DAPT:

N-[N-(3,5-Difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester

Hg:

High glucose

Ng:

Normal glucose

NC:

Negative control

ECs:

Endothelial cells

HUVECs:

Human umbilical vascular ECs

DR:

Diabetic retinopathy

BM:

Basement membrane

MMP:

Matrix metalloprotease

RBP-Jκ:

Recombination signal-binding protein Jκ

Dll4:

Delta-like 4

FERM:

Four-point-one, ezrin, radixin, moesin

TNFα:

Tumor necrosis factor α

PECAM-1:

Platelet endothelial cell adhesion molecule 1

CD31:

Cluster of differentiation 31

CKO:

Conditional knockout

IHC:

Immunohistochemistry

IF:

Immunofluorescence

WB:

Western blotting

AIA:

Angiogenesis invasion assay

QRT-PCR:

Quantitative real time-polymerase chain reaction

IP:

Immunoprecipitation

CHX:

Cycloheximide

HIF-1α:

Hypoxia inducible factor-1α

EdU:

5-Ethynyl-29-deoxyuridine

SiRNA:

Small interfering RNA

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Acknowledgements

We thank Prof. Deng Yi, Prof. Ji Shengjian and master student Long Gaoxin of Southern University of Science and Technology (SUSTech) for technical assistance. We acknowledge the assistance of Core Research Facilities of Southern University of Science and Technology.

Funding

This work was supported, in part, by the National Key Research and Development Program of China Grants (2019YFA0906001), National Natural Science Foundation of China Grants (82022047 and 81972100), Guangdong Provincial Science and Technology Innovation Council Grant (2017B030301018).

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Author notes

  1. Yuechao Dong, Guixing Ma, Xiaoting Hou and Yingying Han contributed equally to this study.

Authors and Affiliations

  1. Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, 518055, China

    Yuechao Dong, Guixing Ma, Xiaoting Hou, Yingying Han, Zhen Ding, Wanze Tang, Litong Chen, Yangshan Chen, Bo Zhou, Kaosheng Lv, Changzheng Du & Huiling Cao

  2. Southern University of Science and Technology, Shenzhen, 518055, China

    Feng Rao

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  1. Yuechao Dong
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Contributions

YD, GM and HC contributed to study design. YD, GM, XH, YH, ZD, WT, YC and HC contributed to study conducts, data collection and analysis. YD, XH, YH, FR, KL, CD, GM and HC contributed to data interpretation. Drafting the manuscript: YD, HC and GM. DY, GM and HC take the responsibility for the integrity of the data analysis.

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Correspondence to Guixing Ma or Huiling Cao.

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Dong, Y., Ma, G., Hou, X. et al. Kindlin-2 controls angiogenesis through modulating Notch1 signaling. Cell. Mol. Life Sci. 80, 223 (2023). https://doi.org/10.1007/s00018-023-04866-w

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