Inhibition of arterial cells proliferation in vivo in injured arteries by hyaluronan fragments

It has been demonstrated previously that administration of high levels of high molecular mass hyaluronan (hyaluronic acid, HA) to rats was able to reduce in a significant way neointima formation in the injured arteries. In the present study, our aim was to verify whether small forms of HA (4-16 saccharides) are still able to reduce the proliferative response of ASMC to aortic injury. Treated rats received a total of 8 injections of a fixed dose of HA fragments (27 mg/kg rat contained in a volume of 550 mul). Two injections were given on the day of balloon catheter injury (BCI): one, intravenous, 10 min before BCI and one, subcutaneous, immediately after the BCI. The others injections (subcutaneous) were at 2, 4, 6, 8, 10 and 12 days after BCI. Control rats received an equivalent volume of the dissolving buffer containing only hyaluronidase, which has been destroyed before injection to rats. Neointima formation was analysed 14 days after the BCI. Intima-media wet weight and DNA content were significantly reduced in rats receiving HA fragments in comparison to controls (2P = 0.01 for wet weight and 0.03 for DNA). This finding was confirmed by the histomorphometric study which showed that both neointima area and the ratio neointima/neointima + media were significantly decreased in treated rats (2P = 0.03 for intima area and 0.049 for the ratio). Our data showed thus and for the first time that administration of HA fragments with a very low molecular mass (4-16 saccharides) reduces the proliferative reaction of aorta to injury in vivo. In conclusion, HA fragments, which are components with an excellent safety profile, may offer hope for the prevention of restenosis after angioplasty. (C) 2003 Elsevier Ireland Ltd. All rights reserved.