Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease

We investigated a transgenic mouse model of sickle cell disease, homozygous for deletion of mouse beta -globin and containing transgenes for human bet a (S) and beta (S-antilles) globins linked to the transgene for human alpha -globin. In these mice, basal cGMP production in aortic rings is increased , whereas relaxation to an endothelium-dependent vasodilator, A-23187, is i mpaired. In contrast, aortic expression of endothelial nitric oxide synthas e (NOS) is unaltered in sickle mice, whereas expression of inducible NOS is not detected in either group; plasma nitrate/nitrite concentrations and NO S activity are similar in both groups. Increased cGMP may reflect the stimu latory effect of peroxides (an activator of guanylate cyclase), because lip id peroxidation is increased in aortae and in plasma in sickle mice. Despit e increased vascular cGMP levels in sickle mice, conscious systolic blood p ressure is comparable to that of aged-matched controls; sickle mice, howeve r, evince a greater rise in systolic blood pressure in response to nitro-L- arginine methyl ester, an inhibitor of NOS. Systemic concentrations of the vasoconstrictive oxidative product 8-isoprostane are increased in sickle mi ce. We conclude that vascular responses are altered in this transgenic sick le mouse and are accompanied by increased lipid peroxidation and production of cGMP; we suggest that oxidant-inducible vasoconstrictor systems such as isoprostanes may oppose nitric oxide-dependent and nitric oxide-independen t mechanisms of vasodilatation in this transgenic sickle mouse. Destabiliza tion of the vasoactive balance in the sickle vasculature by clinically rele vant states may predispose to vasoocclusive disease.