Activation of mitogenic and antimitogenic pathways in cyclically stretchedarterial smooth muscle

Biophysical forces regulate vascular smooth muscle cell (VSMC) physiology a nd evoke vascular remodeling. Two VSMC autocrine molecules, insulin-like gr owth factor I (IGF-I) and nitric oxide (NO), are implicated in remodeling a ttributable to VSMC hyperplasia. We investigated the role of in vitro cycli c stretch on rat VSMC IGF-I, NO, and cellular growth. Cyclic stretch (1 Hz at 120% resting length for 48 h) stimulated VSMC proliferation 2.5-fold vs. unstretched cells and was accompanied by a 1.8-fold increase in VSMC IGF-I secretion. Despite activation of this proliferative pathway, cyclic stretc h induced inducible (i) nitric oxide synthase (NOS) expression and a twofol d increase in NO secretion, a molecule with documented antiproliferative ef fects. Cytokine treatment enhanced iNOS expression and NO secretion while i nhibiting vascular growth by approximate to 50% in static cells. Cytokine t reatment of stretched VSMC enhanced NO secretion 2.5-fold while inhibiting growth by approximate to 80%. Exogenous IGF-I increased NOS activity 1.5-fo ld and NO secretion 8.5-fold in static cells. In turn, iNOS inhibition incr eased IGF-I secretion 1.6-fold and enhanced VSMC growth 1.6-fold in stretch ed cells. An NO donor (sodium nitroprusside) similarly inhibited VSMC proli feration in static (24%) and stretched (50%) VSMC while also inhibiting IGF -I secretion from stretched cells by approximate to 35%. Thus cyclic stretc h stimulates mitogenic (IGF-I) and antimitogenic (NO) pathways in VSMC. The se two molecules regulate each other's secretory rates, providing tight reg ulation of VSMC proliferation. These data may have profound implications in understanding vascular growth alterations in vascular injury and hypertens ion.