Expression of granulocyte colony-stimulating factor is induced in injured rat carotid arteries and mediates vascular smooth muscle cell migration

Abstract

Granulocyte colony-stimulating factor (G-CSF) is a lineage-restricted hematopoietic growth factor that stimulates proliferation and maturation of hematopoietic progenitors and is a known powerful mobilizer of bone marrow-derived stem cells. Very little has been reported on G-CSF expression and modulation of vascular smooth muscle cell (VSMC) activation. The purpose of this study was to characterize the expression and effects of G-CSF on primary human VSMC and balloon angioplasty-injured rat carotid arteries. In cultured human VSMC, G-CSF mRNA and protein expression are induced by several cytokines, with the most potent being fetal calf serum and T-lymphocyte-conditioned media. G-CSF is not expressed in naive rat carotid arteries but is induced in neointimal SMC in carotid arteries subject to balloon angioplasty. G-CSF is chemotactic for human VSMC. There is a significant difference between unstimulated cells and those treated with G-CSF at 100 and 1,000 pg/ml (P < 0.01 and 0.05 for 3 experiments). G-CSF also activates the GTPase Rac1, a regulator of cellular migration in VSMC. Inhibition of Rac1 inhibits G-CSF-driven VSMC migration. Important signal transduction protein kinases, including p44/42 MAPK, Akt, and S6 kinase, are also activated in response to G-CSF. This is the first report describing the expression of G-CSF in injured arteries and the multiple effects of G-CSF on VSMC activation. Together, our data suggest that G-CSF is an important mediator of inflammatory cell-VSMC communication and VSMC autocrine activation and may be an important mediator of the VSMC response to injury.

The ability of AIF-1 to activate human vascular smooth muscle cells is lost by mutations in the EF-hand calcium-binding region

“…VSMC in uninjured arteries do not express G-CSF, but in response to injury or cytokine stimulation, VSMC are capable of G-CSF expression [38]. We have previously shown that over-expression of AIF-1 in human VSMC can induce G-CSF expression and secretion [12].…”

Granulocyte colony-stimulating factor for ischemic heart failure: should we use it?

“…These results triggered an alert for G-CSF treatments. It has been reported that G-CSF could activate and induce the proliferation of vascular smooth muscle cells in injured arteries [76,77]. Increased neointimal formation and in-stent restenosis in coronaries treated with bare, but drug-eluting stents were observed in G-CSF-treated pigs submitted to myocardial infarction [78].…”

Mobilization of CD34-Positive Bone Marrow–Derived Cells After Coronary Stent Implantation

“…29 It has been demonstrated that the expression of G-CSF is induced in the local arterial wall by injury. 30 Thus, endogenous G-CSF production by stentinduced injury might also contribute to mobilization of CD34-positive cells and restenosis.…”