PDGF‐BB induces vascular smooth muscle cell expression of high molecular weight FGF‐2, which accumulates in the nucleus

Abstract

Basic fibroblast growth factor (FGF-2) and platelet-derived growth factor (PDGF) are implicated in vascular remodeling secondary to injury. Both growth factors control vascular endothelial and smooth muscle cell proliferation, migration, and survival through overlapping intracellular signaling pathways. In vascular smooth muscle cells PDGF-BB induces FGF-2 expression. However, the effect of PDGF on the different forms of FGF-2 has not been elucidated. Here, we report that treatment of vascular aortic smooth muscle cells with PDGF-BB rapidly induces expression of 20.5 and 21 kDa, high molecular weight (HMW) FGF-2 that accumulates in the nucleus and nucleolus. Conversely, PDGF treatment has little or no effect on 18 kDa, low-molecular weight FGF-2 expression. PDGF-BB-induced upregulation of HMW FGF-2 expression is controlled by sustained activation of extracellular signal-regulated kinase (ERK)-1/2 and is abolished by actinomycin D. These data describe a novel interaction between PDGF-BB and FGF-2, and indicate that the nuclear forms of FGF-2 may mediate the effect of PDGF activity on vascular smooth muscle cells.

The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia–reperfusion injury

“…These studies suggest that the LMW and the HMW isoforms might work in opposition during I/R injury to modulate cardiac function. It has been speculated that HMW and LMW FGF2 may serve different functions by controlling each other's biological activity [30, 31], a supposition supported by our work here showing an increase in total LMW FGF2 protein in the absence of HMW FGF2, as well as the finding that overexpression of HMW FGF2 reduces FGFR1 activation, through which LMW FGF2 cardioprotection from I/R injury is mediated.…”

“…This observation is similar to our current findings which showed that the LMW and HMW isoforms may act on the heart through different modes of action. The HMW and LMW FGF2 isoforms are speculated to associate, either directly or indirectly, in a reciprocal mechanism, controlling each other's biological activity in a concentration- and/or localization-dependent manner [31, 32]. Therefore, the presence or absence of the HMW FGF2 isoforms may affect the biological function of the LMW isoform in the heart as demonstrated in the current study by the alteration in FGF receptor activation (Figure 6A) or post-ischemic recovery of cardiac function (Figure 2).…”

Functional diversity of FGF‐2 isoforms by intracellular sorting

“…The FGF-2 expression was mediated by sustained activation of ERK-1/2 and was abolished by actinomycin D. PDGF-AA that transiently activated ERK-1/2 in these cells did not influence the FGF-2 expression level. (43) Interestingly, it was shown that the expression of 22, 22.5 and 24 kDa FGF-2 decreased in a cell-density-dependent manner in normal cells, but not in tumor cells or cells transformed with SV40 large T antigen. (44) H-ras transformed Rat-1 fibroblasts expressed increased level of hmw FGF-2 in comparison to the normal fibroblast.…”

Mechanisms of Vascular Smooth Muscle Cell Migration

“…28 PDGF acts indirectly to induce synthesis of epidermal growth factor and fibroblast growth factor-2, both of which enhance cell migration. 29 This is only one example of the well-documented ability of growth factors and cytokines to stimulate their own synthesis by smooth muscles, as well as synthesis of other growth factors and cytokines. 30,31 Therefore, both direct and indirect effects of signaling proteins on VSM migration are very likely to occur in vivo during a response to injury or inflammation.…”