Smooth muscle-targeted overexpression of insulin-like growth factor I results in enhanced vascular contractility

Insulin-like growth factor I (IGF-I) has been postulated to function as a v asodilator. We explored the vasoactive effects of chronic elevations of art erial IGF-I levels in SMP8-IGF-I mice, in which IGF-I is overexpressed in s mooth muscle (SM) by means of a SM alpha -actin promoter. Denuded aortas fr om SMP8-IGF-I mice generated increased force in response to KCI or phenylep hrine and had greater sensitivity to KCl depolarization. This is not due to desensitization of a SM NO pathway, as pretreatment with n-omega -nitro-L- arginine affected both wild-type and SMP8-IGF-I aortas to a similar degree. The increased contractility ex vivo is not associated with changes in hear t rate or blood pressure. Total smooth muscle myosin heavy chain (SMHC) mes senger RNA (mRNA) was greater in SMP8-IGF-I aortas, with preferential expre ssion of SMHC-A. Reciprocal effects on contractility and SMHC mRNA were obs erved in SMP8-IGFBP-4 animals, in which IGF-binding protein-4 was overexpre ssed through the same promoter. Also, SM cu-actin mRNA was increased in the aortas from SMP8-IGF-I mice. In summary, chronic arterial overexpression o f IGF-I is associated with increased contractility. These effects differ fr om those seen after acute exposure to the growth factor and may relate to I GF-mediated changes in expression and relative isoform abundance of critica l contractile proteins.