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Kindlin-2 controls angiogenesis through modulating Notch1 signaling.

Yuechao Dong1, Guixing Ma2, Xiaoting Hou1

  • 1Department 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.

Cellular and Molecular Life Sciences : CMLS
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PubMed
Summary

Kindlin-2 is crucial for physiological angiogenesis, a process vital for development. Its deficiency impairs blood vessel formation, highlighting Kindlin-2 as a therapeutic target for diseases like diabetic retinopathy.

Keywords:
AngiogenesisEndothelial Kindlin-2NICDNotch1

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Area of Science:

  • Vascular Biology
  • Developmental Biology
  • Cell Signaling

Background:

  • Kindlin-2's role in organ development is established, but its function in angiogenesis remains unclear.
  • Angiogenesis, the formation of new blood vessels, is essential for physiological processes and disease pathology.
  • Notch signaling is a key pathway regulating angiogenesis.

Purpose of the Study:

  • To investigate the role of Kindlin-2 in Notch-mediated physiological angiogenesis.
  • To elucidate the molecular mechanisms by which Kindlin-2 regulates angiogenesis.
  • To assess the therapeutic potential of targeting Kindlin-2 in angiogenic diseases.

Main Methods:

  • Endothelial-cell-specific Kindlin-2 deletion in mouse models.
  • In vitro studies using human umbilical vein endothelial cells (HUVECs).
  • Immunofluorescence staining, Western blotting, and treatment with γ-secretase inhibitor (DAPT).

Main Results:

  • Kindlin-2 deficiency in endothelial cells leads to embryonic lethality due to impaired angiogenesis.
  • Kindlin-2 enhances vascular endothelial growth factor A-induced endothelial cell functions (migration, proteolysis, morphogenesis, sprouting).
  • Kindlin-2 stabilizes NOTCH1, inhibiting Notch intracellular domain release and promoting angiogenesis.
  • High glucose-induced hyperactive angiogenesis is mediated by increased Kindlin-2 expression.

Conclusions:

  • Kindlin-2 is essential for Notch-mediated physiological angiogenesis during development.
  • Kindlin-2 acts by maintaining NOTCH1 integrity, thereby regulating downstream signaling.
  • Kindlin-2 is a potential therapeutic target for angiogenic diseases, including diabetic retinopathy.