Pulsatile and steady flow induces c‐fos expression in human endothelial cells

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Abstract
The effects of pulsatile and steady fluid flow on the mRNA levels of proto‐oncogenes c‐fos, c‐jun, and c‐myc in cultured human umbilical vein endothelial cells (HUVEC) were investigated. c‐fos mRNA levels in stationary cultures were very low. A 1 Hz pulsatile flow with an average shear stress of 16 dynes/cm2 induced a dramatic increase of c‐fos mRNA levels in HUVEC 0.5 h after the onset of flow, which declined rapidly to basal levels within 1 h. Steady flow with a similar shear stress also induced a transient increase of c‐fos mRNA levels, but to a lesser extent. In addition, increased, c‐fos mRNA levels were observed when low shear (2–6 dynes/cm2) was replaced by high shear (16–33 dynes/cm2). Pulsatile and steady flow caused a slight increase of c‐jun and c‐myc mRNA levels. The role of pulsatility was also investigated in platelet‐derived growth factor (PDGF) expression. Pulsatile flow induced a transient increase of PDGF A‐ and B‐chain mRNA levels with peaks at 1.5–2 h. Pulsatile flow, which was more stimulatory in mediating c‐fos expression, however, was less stimulatory than steady flow in mediating PDGF expression. By using various inhibitors, protein kinase C was found to be an important mediator in flow‐induced c‐fos expression, with the involvement of G proteins, phospholipase C, and intracellular calcium. Protein kinase C was previously shown as a possible major mediator in flow‐induced PDGF expression which, at least partly, appeared to follow the induction mechanism of c‐fos, suggesting a possible connection between c‐fos and PDGF induction. However, the c‐fos antisense treatment, which significantly inhibited c‐fos transcription, failed to block the flow‐induced PDGF expression, suggesting that flow‐induced c‐fos expression may not play an important role in the mechanism of flow‐induced PDGF expression. The difference in the induction of c‐fos and PDGF expression under pulsatile as compared to steady flow indicates of c‐fos and PDGF expression under pulsatile as compared to steady flow indicates that a complex, flow‐mediated regulatory mechanism of gene expression exists in HUVEC. The increased expression of these proto‐oncogenes mediated by flow may be important in regulating long‐term cellular responses.