Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor

TLDR

VEGF was first identified as a vascular permeability factor, yet the specific vessel types and endothelial morphological changes it induces in vivo remain incompletely characterized. Topical or intradermal VEGF‑165 rapidly increases permeability of postcapillary venules, muscular venules, and capillaries and induces fenestration of small venular and capillary endothelia within 10 minutes—an effect absent with histamine, saline, or heat‑inactivated VEGF, and fully blocked by anti‑VEGF antibodies, distinguishing it from other mediators.

Abstract

The vascular endothelial growth factor (VEGF) was originally described as vascular permeability factor due to its ability to increase microvascular permeability to plasma proteins. However, the vessel types (arteriolar, venular, and capillary) affected by VEGF and the modification of endothelial morphology in response to increased permeability induced by VEGF in vivo have not been precisely documented. By topical application or intradermal injection of recombinant human VEGF-165 we find that VEGF increases the permeability of postcapillary venules as well as muscular venules and capillaries. Surprisingly, we also find that endothelia of small venules and capillaries become fenestrated within 10 minutes of VEGF application. Fenestrations appeared in vascular beds which do not normally have fenestrated endothelium, namely the cremaster muscle and skin. Histamine, saline, and heat-inactivated VEGF do not cause fenestrations. Increased permeability is completely inhibited when VEGF is cleared by immunoprecipitation with anti-VEGF monoclonal antibodies. The VEGF effect on permeability is unlike that of any other mediator described to date since both muscular venules and capillaries are affected.