Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells.
Both nitric oxide (NO) and carbon monoxide (CO) are vessel wall-derived messenger molecules that cause platelet inhibition and vasodilation by activating guanylyl cyclase in target cells. Since vascular smooth muscle cells (SMCs) are exposed to shear and tensile stresses, this study examined the effects of these hemodynamic forces on the enzymes that generate NO and CO in SMCs. Monolayers of cultured rat aortic SMCs were subjected to shear stress using a modified cone and plate viscometer, or cyclic elongational stretch using a compliant silastic culture membrane. Shear stress stimulated time-dependent increases in mRNA and protein for inducible heme oxygenase-1 (HO-1), the enzyme which forms CO as a byproduct of heme degradation. The threshold level of shear necessary to induce HO-1 expression was between 5 and 10 dynes/cm2. In contrast, shear stress did not stimulate inducible NO synthase (iNOS) expression. Cyclic stretch also induced the expression of HO-1 but not of iNOS mRNA. Exposure of vascular SMCs to shear stress stimulated the production and release of CO as demonstrated by the CO-dependent increase in intracellular cGMP levels in coincubated platelets. In addition, ADP-stimulated aggregation was inhibited in platelets exposed to sheared SMCs but not in platelets exposed to untreated control SMCs. Treatment of sheared SMCs with the HO-1 inhibitor, tin protoporphyrin-IX, blocked the antiaggregatory effect of the cells, whereas the iNOS inhibitor, methyl--arginine, had no effect. These results indicate that hemodynamic forces induce HO-1 gene expression and CO production in vascular SMCs, and that SMC-derived CO inhibits platelet aggregation. Thus, CO is a novel endogenous vessel wall-derived messenger molecule that may be selectively induced by hemodynamic forces to inhibit platelet reactivity and preserve blood fluidity at sites of vascular injury.
Wagner
C T
CT
Cox Laboratory for Biomedical Engineering, Rice University, Houston, Texas 77251, USA.
Durante
W
W
Christodoulides
N
N
Hellums
J D
JD
Schafer
A I
AI
D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D006439:Hemodynamics; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000503:physiopathology*; D010974:Platelet Aggregation; D051381:Rats; D013314:Stress, Mechanical
D017077:Culture Media, Conditioned; D006419:Heme Oxygenase (Decyclizing)