Cholesterol crystals increase vascular permeability by inactivating SHP2 and disrupting adherens junctions

Arul M. Mani, Rima Chattopadhyay, Nikhlesh Singh, Rao Gadiparthi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

To understand the adverse effects of cholesterol crystals on vascular homeostasis, we have studied their effects on endothelial barrier function. Cholesterol crystals increased endothelial barrier permeability in a dose and time dependent manner. In addition, cholesterol crystals induced tyrosine phosphorylation of VE-cadherin and α-catenin, disrupting endothelial AJ and its barrier function and these effects required xanthine oxidase-mediated H2O2 production, SHP2 inactivation and Frk activation. Similarly, feeding C57BL/6 mice with cholesterol-rich diet increased xanthine oxidase expression, H2O2 production, SHP2 inactivation and Frk activation leading to enhanced tyrosine phosphorylation of VE-cadherin and α-catenin, thereby disrupting endothelial AJ and increasing vascular permeability. Resolvin D1, a specialized proresolving mediator, prevented all these adverse effects of cholesterol crystals and cholesterol-rich diet in endothelial cells and mice, respectively. Based on these observations, it is likely that cholesterol crystals via disrupting AJ increase vascular permeability, a critical event of endothelial dysfunction and specialized proresolving mediators such as Resolvin D1 exert protection against these effects.

Original languageEnglish (US)
Pages (from-to)72-84
Number of pages13
JournalFree Radical Biology and Medicine
Volume123
DOIs
StatePublished - Aug 1 2018

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Adherens Junctions
Capillary Permeability
Cholesterol
Crystals
Catenins
Phosphorylation
Xanthine Oxidase
Nutrition
Tyrosine
Chemical activation
Diet
Endothelial cells
Inbred C57BL Mouse
Blood Vessels
Permeability
Homeostasis
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

Cholesterol crystals increase vascular permeability by inactivating SHP2 and disrupting adherens junctions. / Mani, Arul M.; Chattopadhyay, Rima; Singh, Nikhlesh; Gadiparthi, Rao.

In: Free Radical Biology and Medicine, Vol. 123, 01.08.2018, p. 72-84.

Research output: Contribution to journalArticle

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AB - To understand the adverse effects of cholesterol crystals on vascular homeostasis, we have studied their effects on endothelial barrier function. Cholesterol crystals increased endothelial barrier permeability in a dose and time dependent manner. In addition, cholesterol crystals induced tyrosine phosphorylation of VE-cadherin and α-catenin, disrupting endothelial AJ and its barrier function and these effects required xanthine oxidase-mediated H2O2 production, SHP2 inactivation and Frk activation. Similarly, feeding C57BL/6 mice with cholesterol-rich diet increased xanthine oxidase expression, H2O2 production, SHP2 inactivation and Frk activation leading to enhanced tyrosine phosphorylation of VE-cadherin and α-catenin, thereby disrupting endothelial AJ and increasing vascular permeability. Resolvin D1, a specialized proresolving mediator, prevented all these adverse effects of cholesterol crystals and cholesterol-rich diet in endothelial cells and mice, respectively. Based on these observations, it is likely that cholesterol crystals via disrupting AJ increase vascular permeability, a critical event of endothelial dysfunction and specialized proresolving mediators such as Resolvin D1 exert protection against these effects.

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