Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia.
Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4+ T-lymphocytes and epidermal CD8+ lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy.
Kunstfeld
Rainer
R
Cutaneous Biology Research Center, Massachusetts General Hospital, Bldg 149, 13th St, Charlestown, MA 02129, USA.
Hirakawa
Satoshi
S
Hong
Young-Kwon
YK
Schacht
Vivien
V
Lange-Asschenfeldt
Bernhard
B
Velasco
Paula
P
Lin
Charles
C
Fiebiger
Edda
E
Wei
Xunbin
X
Wu
Yan
Y
Hicklin
Daniel
D
Bohlen
Peter
P
Detmar
Michael
M
D000818:Animals; D002199:Capillary Permeability; D002634:Chemotaxis, Leukocyte; D002908:Chronic Disease; D003872:Dermatitis / Q000473:pathology*; D004195:Disease Models, Animal; D003875:Drug Eruptions / Q000473:pathology; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005260:Female; D006965:Hyperplasia / Q000209:etiology; D006968:Hypersensitivity, Delayed; D007249:Inflammation / Q000209:etiology*; D042601:Lymphatic Vessels / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011565:Psoriasis / Q000473:pathology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology
D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040262:Receptors, Vascular Endothelial Growth Factor