Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds.

Abstract

Some human chronic dermal wounds treated with recombinant platelet-derived growth factor-BB (rPDGF-BB) show increased healing coupled with fibroblast activation and granulation tissue formation. To determine whether endogenous PDGF is associated with healing and nonhealing dermal ulcer phenotypes, we developed monoclonal antibodies capable of recognizing the three isoforms of PDGF, AA, AB, and BB dimers, and capable of discriminating between two alternatively spliced A chain transcripts. We detected little PDGF isoform expression in normal skin and in nonhealing dermal ulcers. In contrast, in surgically created acute wounds and chronic ulcers treated with rPDGF-BB, markedly upregulated levels of PDGF-AA (long form) were found. In both types of wounds, increased PDGF-AA was detected primarily in capillaries and fibroblasts, although in rPDGF-BB-treated chronic wounds, widespread expression of PDGF-AA was somewhat delayed. With continued treatment, the long form of PDGF-AA, which can preferentially bind extracellular matrix, was expressed only in capillaries, while fibroblasts began synthesizing the short form of PDGF-AA. Within capillaries, all endothelial cells and varying numbers of pericytes and smooth muscle cells contained PDGF-AA. In all wounds, macrophages and keratinocytes were not a major contributor. While PDGF-BB and PDGF-AB were present in a minority of healing wounds, they were usually present at lower levels than PDGF-AA. PDGF-18 receptors, which bind only PDGF-BB and not other isoforms, were found in normal skin and granulation tissue, providing a molecular basis for treating human chronic wounds with exogenous rPDGF-BB. (J. Clin.

α5 and α2 Integrin Gene Transfers Mimic the PDGF-B–Induced Transformed Phenotype of Fibroblasts in Human Skin

“…Extraction of PDGF from human skin after injection with PDGF-B/Ad5 in this study demonstrated that PDGF isoforms are indeed expressed at higher levels than in LacZ/Ad5-transduced samples. Further, we have shown that the adenoviral transfer of PDGF-B not only induced PDGF-A, but also PDGF-R␣ expression in fibroblasts, which is in accordance with a previous report about the induction of native PDGF-A by exogenous PDGF-B (Pierce et al, 1995). Therefore, fibroblasts may amplify the effects of PDGF-B through PDGF receptors expressed on these cells.…”

“…PDGF-B increases production of fibronectin in cells (Allen-Hoffmann et al, 1990) and enhances collagen synthesis as part of the wound-healing response (Pierce et al, 1995). We hypothesized that the phenotype induced in vivo by PDGF-B in fibroblasts is due to the up-regulation of integrin ␣5 and ␣2 subunits, which, in turn, increase fibronectin and collagen production.…”

“…In the absence of fibronectin, ␣5␤1 integrin expression induces a negative growth signal that can only be overcome when cells are provided with fibronectin (Allen-Hoffmann et al, 1990;Juliano and Varner, 1993;Varner et al, 1995). PDGF-B increases production of fibronectin in cells (Allen-Hoffmann et al, 1990) and enhances collagen synthesis as part of the wound-healing response (Pierce et al, 1995). We hypothesized that the phenotype induced in vivo by PDGF-B in fibroblasts is due to the up-regulation of integrin ␣5 and ␣2 subunits, which, in turn, increase fibronectin and collagen production.…”

Recombinant AAV vector encoding human VEGF165 enhances wound healing

“…DOI: 10.1038/sj/gt/3301697 angiogenic growth factors from macrophages and keratinocytes and its impairment leads to a delay in skin repair. [7][8][9][10][11] One of the essential growth factors which are involved in the angiogenetic process in the wounded tissues is vascular endothelial growth factor (VEGF), 12 which promotes proliferation and migration of endothelial cells resulting in the formation of a capillary network which is an essential requisite for the healing process.…”

Adeno-associated viral vector-mediated human vascular endothelial growth factor gene transfer stimulates angiogenesis and wound healing in the genetically diabetic mouse

“…The formation of new blood vessels provides a route for oxygen and nutrient delivery, as well as a conduit for components of the inflammatory response. Healing is concomitant with an increasing release of angiogenic growth factors from macrophages and keratinocytes and its impairment leads to a delay in skin repair [3,4,5,6,7]. Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic cytokines which promotes all steps in the angiogenic cascade [8].…”