Impact of Fibroblast Growth Factor-Binding Protein–1 Expression on Angiogenesis and Wound Healing

Abstract

Fibroblast growth factors (FGFs) participate in embryonic development, in maintenance of tissue homeostasis in the adult, and in various diseases. FGF-binding proteins (FGFBP) are secreted proteins that chaperone FGFs stored in the extracellular matrix to their receptor, and can thus modulate FGF signaling. FGFBP1 (alias BP1, FGF-BP1, or HBp17) expression is required for embryonic survival, can modulate FGF-dependent vascular permeability in embryos, and is an angiogenic switch in human cancers. To determine the function of BP1 in vivo, we generated tetracycline-regulated conditional BP1 transgenic mice. BP1-expressing adult mice are viable, fertile, and phenotypically indistinguishable from their littermates. Induction of BP1 expression increased mouse primary fibroblast motility in vitro, increased angiogenic sprouting into subcutaneous matrigel plugs in animals and accelerated the healing of excisional skin wounds. FGF-receptor kinase inhibitors blocked these effects. Healing skin wounds showed increased macrophage invasion as well as cell proliferation after BP1 expression. Also, BP1 expression increased angiogenesis during the healing of skin wounds as well as after ischemic injury to hindlimb skeletal muscles. We conclude that BP1 can enhance FGF effects that are required for the healing and repair of injured tissues in adult animals. The family of fibroblast growth factors (FGFs) encompasses 18 distinct FGF receptor ligands, with a wide expression range and a significant role in angiogenesis, tumor progression, wound healing, and embryonic development.1-4 Many members of the FGF family, such as FGF1 and FGF2, are immobilized in the extracellular matrix (ECM) bound to heparan sulfate proteoglycans (HSPGs) and released from this storage site by proteases and heparanases. 4 -6 The involvement of carrier proteins that shuttle FGFs from their storage site to their receptors represents an alternative mode of regulation of FGF release from the ECM. 1,7 FGF-binding protein 1 (BP1, FGFBP1, FGF-BP1, or HBp17), 8 the best characterized of the three known secreted FGFBPs, 9 is an extracellular chaperone that binds FGF1, 2, 7, 10, and 22 in a reversible, noncovalent manner. 8,10 -12 Binding of the C-terminus of the BP1 protein is sufficient for its interaction with FGF2.13 After binding to BP1, the biochemical and biological activities of FGF are positively modulated.14 Several findings from different laboratories indicate that BP1 can contribute to embryonic development, 15 angiogenesis, tumor growth, and malignant progression, 11,12,14 -20 as well as the maintenance and reinnervation of the neuromuscular junction. 21 We reported earlier that expression of BP1 in SW13 cells induces FGF2 release from the cells, FGF-dependent colony formation in soft agar, and the growth of highly vascularized tumors in nude mice.11 In contrast, depletion of endogenous BP1 from ME180 cells was observed to reduce the release of ECM bound FGF2 into the cell supernatants and to increase FGF2 immobilized on the cell surface.16 Consisten...

Effects of Differential Distribution of Microvessel Density, Possibly Regulated by miR-374a, on Breast Cancer Prognosis

“…New vessel formation (angiogenesis) is an essential physiological process in embryonic development, normal growth, and tissue repair (Tassi et al, 2011). Angiogenesis is tightly regulated at the molecular level; however, this process is dysregulated in several pathological conditions such as cancer (Rapisarda et al, 2012).…”

A Novel Enhancer of the Wound Healing Process

“…In addition, exogenously added FGF-BP1 enhances keratinocyte migration. 16 Together with the finding that expression levels of the fgfbp1 transgene were particularly high in keratinocytes of the epidermis and the hair follicles, 6 this finding indicates that re-epithelialization may also be accelerated in the FGF-BP1 transgenic mice. Indeed, the accelerated wound closure that was observed in these animals supports this hypothesis, although it remains to be determined whether this resulted from enhanced contraction and/or from enhanced re-epithelialization.…”

“…Thus, Tassi et al 6 also demonstrated that FGF-BP1 enhances angiogenesis in the mouse ischemic hindlimb muscles. Furthermore, the expression of FGF-BP is increased in regenerating renal tubular epithelial cells, indicating a role in kidney repair.…”

“…A contribution of wound contraction seems likely because rodent wounds heal predominantly by contraction and because the number of contractile myofibroblasts was strongly increased on induction of FGF-BP1 expression. 6 Interestingly, the effect of FGF-BP1 on wound repair was abolished when the mice were treated with an FGFR kinase inhibitor, strongly suggesting that the FGF-BP1-induced acceleration of the wound healing process is FGF dependent. In the future, it will be interesting to identify the type of FGF(s) that is (are) positively regulated by FGF-BP1 in healing wounds.…”

“…Furthermore, FGFs are frequently expressed in small amounts, and enhancement of their receptor affinity, which is also achieved by FGF-BPs, may allow them to exert important biological functions at extremely low concentrations. In this issue of The American Journal of Pathology, Tassi et al 6 demonstrate that FGF-BP1 promotes angiogenesis and wound repair through acceleration of FGF signaling.…”