Increased Microvascular Density and Enhanced Leukocyte Rolling and Adhesion in the Skin of VEGF Transgenic Mice

Abstract

Vascular endothelial growth factor (VEGF) has been implicated in the pathologic angiogenesis observed in psoriasis and other chronic inflammatory skin diseases that are characterized by enhanced expression of VEGF by epidermal keratinocytes and of VEGF receptors by tortuous microvessels in the upper dermis. To investigate the functional importance of chronic VEGF overexpression in vivo, we used a keratin 14 promoter expression cassette containing the gene for murine VEGF164 to selectively target VEGF expression to basal epidermal keratinocytes in transgenic mice. These mice demonstrated an increased density of tortuous cutaneous blood capillaries with elevated expression levels of the high affinity VEGF receptors, VEGFR-1 and VEGFR-2, most prominently during the neonatal period. In contrast, no abnormalities of lymphatic vessels were detected. In addition, the number of mast cells in the upper dermis was significantly increased in transgenic skin. Intravital fluorescence microscopy revealed highly increased leukocyte rolling and adhesion in postcapillary skin venules that were both inhibited after injection of blocking antibodies against E- and P-selectin. Combined blocking antibodies against intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 were without effect, whereas an anti-vascular cell adhesion molecule-1/VLA-4 antibody combination almost completely normalized the enhanced leukocyte adhesion in transgenic mice. This study reveals VEGF as a growth factor specific for blood vessels, but not lymphatic vessels, and demonstrates that chronic orthotopic overexpression of VEGF in the epidermis is sufficient to induce cardinal features of chronic skin inflammation, providing a molecular link between angiogenesis, mast cell accumulation, and leukocyte recruitment to sites of inflammation.

Viral Vascular Endothelial Growth Factor Plays a Critical Role in Orf Virus Infection

“…Orf virus replication is known to be confined to the epidermis (23,24), but our data suggest that the viral VEGF affects endothelial cells of the dermis. This notion is consistent with the results of studies of transgenic mice, in which overexpression of VEGF in keratinocytes stimulated an increase in the density of blood vessels in the dermis (10). Enhanced expression of VEGF has also been reported for a range of malignant and benign tumors of the skin and has been shown for advanced melanoma lesions to directly correlate with a 2.5-fold increase in the vascular density of the associated dermis (11).…”

Angiogenic Actions of Angiopoietin-1 Require Endothelium-Derived Nitric Oxide

“…38 This is consistent with the stabilizing effect of Ang1 on vascular endothelium and its underlying basement membrane. In the Matrigel model, the induction of angiogenesis in response to Ang1 also appeared to produce relatively non-leaky neovessels, because although VEGF and Ang1 resulted in similar increases in vessel number, VEGF-treated Matrigel implants contained significantly greater amounts of FITClabeled dextran.…”

Vascular Endothelial Growth Factor (VEGF)-Induced Retinal Vascular Permeability Is Mediated by Intercellular Adhesion Molecule-1 (ICAM-1)

“…8 Leukocyte adhesion secondary to VEGF has been previously demonstrated in the microvasculature of growing tumors, 18 the corneas of rabbits, 19 and the skin of transgenic mice. 20 Detmar and associates expressed VEGF using the keratin 14 promoter and observed the induction of a vascular cell adhesion molecule-1 (VCAM-1)-mediated leukostasis in the dermis. 20 In a separate study, Melder and associates demonstrated VEGF-induced leukocyte adhesion to tumor vasculature via ICAM-1 and VCAM-1.…”