A critical role of placental growth factor in the induction of inflammation and edema formation

Abstract

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 upregulated 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. (Blood. 2003;101:560-567)

NF-κB contributes to transcription of placenta growth factor and interacts with metal responsive transcription factor-1 in hypoxic human cells

“…PlGF gene expression is inducible upon proinflammatory stimuli as well as by the condition of low intracellular oxygen tensions, termed hypoxia (Green et al, 2001;Oura et al, 2003;Selvaraj et al, 2003). Several years ago, it was found that the transcriptional regulation of PlGF involves metal responsive transcription factor 1 (MTF-1, also termed metal response element binding transcription factor 1, or in short, metal transcription factor 1) as the hypoxic upregulation of PlGF mRNA was shown to be severely reduced in MTF-1 -/-embryonic fibroblasts (Green et al, 2001).…”

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…In a mouse model of cutaneous delayed-type hypersensitivity, keratinocyte-specific overexpression of PlGF increases the inflammatory response and causes pronounced vascular enlargement (Oura et al 2003). Opposite phenotypes are observed in PlGF-deficient mice (Oura et al 2003).…”

Histological and transcriptional study of angiogenesis and lymphangiogenesis in uninvolved skin, acute pinpoint lesions and established psoriasis plaques: An approach of vascular development chronology in psoriasis

“…Placental growth factor (PlGF) is another important mediator of skin angiogenesis [11] that may directly activate VEGFR1, thus potentiating VEGF activity, and that also promotes bone-marrow-derived precursor cells mobilization and monocyte chemotaxis [11,12]. As for VEGF-A, alternative exon splicing produces four isoforms, PlGF-1 to -4, that differ by their binding affinities for heparin [13,14].…”