Doxycycline induces membrane expression of VE-cadherin on endothelial cells and prevents vascular hyperpermeability

Ofer Fainaru*, Irit Adini, Ofra Benny, Lauren Bazinet, Elke Pravda, Robert D'Amato, Judah Folkman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


The endothelium lining blood vessels serves as a barrier against vascular hyperpermeability, and its maintenance is critical to organ health. Inflammatory mediators evoke tissue edema by disrupting the expression of membrane junctional proteins, which mediate binding between endothelial cell membranes. Endothelial cell-cell junctions form a diffusion barrier between the intravascular and interstitial space. To prevent the morbidity and mortality caused by exaggerated vascular permeability associated with pathological states (e.g., inflammatory and hypersensitivity disorders, pulmonary edema, traumatic lung injury, cerebral edema resulting from stroke, and others), it is important to develop therapeutic approaches to stabilize these interendothelial junctions. Vascular endothelial growth factor (VEGF), a potent proangiogenic cytokine, was first described as vascular permeability factor (VPF). Doxycycline, a tetracycline derivative, has been shown to inhibit angiogenesis in both humans and animal models. We now report that oral doxycycline prevents VPF/VEGF-induced vascular permeability, interleukin-2-induced pulmonary edema, and delayed-type hypersensitivity (DTH) in mice. Remarkably, doxycycline also inhibits tumor growth and tumor-associated vascular hyperpermeability. Finally, we show that doxycycline targets the adherens junction in vascular endothelial cells by inducing the total amount of VE-cadherin expression while decreasing the degree of its phosphorylation. The potential of doxycyline as a therapeutic inhibitor of vascular hyperpermeability in human clinical conditions is promising and warrants further studies.

Original languageAmerican English
Pages (from-to)3728-3735
Number of pages8
JournalFASEB Journal
Issue number10
StatePublished - Oct 2008
Externally publishedYes


  • Angiogenesis
  • Delayed-type hypersensitivity
  • Pulmonary edema


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