title: Doxycycline induces membrane expression of VE-cadherin on endothelial cells and prevents vascular hyperpermeability.
abstract: 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.
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, Department of Surgery, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA. ofer.fainaru@childrens.harvard.edu
authors.forename: Ofer
authors.initials: O
authors.lastname: Fainaru
authors.forename: Irit
authors.initials: I
authors.lastname: Adini
authors.forename: Ofra
authors.initials: O
authors.lastname: Benny
authors.forename: Lauren
authors.initials: L
authors.lastname: Bazinet
authors.forename: Elke
authors.initials: E
authors.lastname: Pravda
authors.forename: Robert
authors.initials: R
authors.lastname: D'Amato
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D015820:Cadherins / Q000096:biosynthesis*; D002199:Capillary Permeability / Q000187:drug effects*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004318:Doxycycline / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006968:Hypersensitivity, Delayed / Q000473:pathology / Q000517:prevention & control; D007376:Interleukin-2 / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D011654:Pulmonary Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D000099152:Cadherin 5
chemical_list: D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D015820:Cadherins; D004318:Doxycycline; D007376:Interleukin-2; D000099152:Cadherin 5