Kindlin-2 controls angiogenesis through modulating Notch1 signaling

Dong，Yuechao1; Ma，Guixing1; Hou，Xiaoting1; Han，Yingying1; Ding，Zhen1; Tang，Wanze1; Chen，Litong1; Chen，Yangshan1; Zhou，Bo1; Rao，Feng2; Lv，Kaosheng1; Du，Changzheng1; Cao，Huiling1

2023-08-01

10.1007/s00018-023-04866-w

Cellular and Molecular Life Sciences   Impact Factor & Quartile

1420-682X

1420-9071

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.

Angiogenesis Endothelial Kindlin-2 NICD Notch1

SCI

English

First ; Corresponding

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:001048810800004

SPRINGER BASEL AG

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85165317577

Scopus

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

Dong，Yuechao,Ma，Guixing,Hou，Xiaoting,et al. Kindlin-2 controls angiogenesis through modulating Notch1 signaling[J]. Cellular and Molecular Life Sciences,2023,80(8).

Dong，Yuechao.,Ma，Guixing.,Hou，Xiaoting.,Han，Yingying.,Ding，Zhen.,...&Cao，Huiling.(2023).Kindlin-2 controls angiogenesis through modulating Notch1 signaling.Cellular and Molecular Life Sciences,80(8).

Dong，Yuechao,et al."Kindlin-2 controls angiogenesis through modulating Notch1 signaling".Cellular and Molecular Life Sciences 80.8(2023).