A critical role of placental growth factor in the induction of inflammation and edema formation.
Angiogenesis is a prominent feature of a number of inflammatory human diseases, including rheumatoid arthritis, psoriasis, and cutaneous delayed-type hypersensitivity (DTH) reactions. Up-regulation of placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, has been found in several conditions associated with pathologic angiogenesis; however, its distinct role in the control of angiogenesis has remained unclear. To directly investigate the biologic function of PlGF in cutaneous inflammation and angiogenesis, DTH reactions were investigated in the ear skin of wild-type mice, of PlGF-deficient mice, and of transgenic mice with targeted overexpression of human PlGF-2 in epidermal keratinocytes, driven by a keratin 14 promoter expression construct. Chronic transgenic delivery of PlGF-2 to murine epidermis resulted in a significantly increased inflammatory response, associated with more pronounced vascular enlargement, edema, and inflammatory cell infiltration than seen in wild-type mice. Conversely, PlGF deficiency resulted in a diminished and abbreviated inflammatory response, together with a reduction of inflammatory angiogenesis and edema formation. VEGF expression was up-regulated at a comparable level in the inflamed skin of all genotypes. These findings reveal that placental growth factor plays a critical role in the control of cutaneous inflammation, and they suggest inhibition of PlGF bioactivity as a potential new approach for anti-inflammatory therapy.
Oura
Hajimu
H
Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129, USA.
Bertoncini
Jennifer
J
Velasco
Paula
P
Brown
Lawrence F
LF
Carmeliet
Peter
P
Detmar
Michael
M
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004487:Edema / Q000209:etiology* / Q000473:pathology; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D006801:Humans; D006968:Hypersensitivity, Delayed; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008222:Lymphokines / Q000096:biosynthesis; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D014161:Transduction, Genetic; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor