title: Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease.
abstract: We investigated a transgenic mouse model of sickle cell disease, homozygous for deletion of mouse beta-globin and containing transgenes for human beta(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 impaired. In contrast, aortic expression of endothelial nitric oxide synthase (NOS) is unaltered in sickle mice, whereas expression of inducible NOS is not detected in either group; plasma nitrate/nitrite concentrations and NOS activity are similar in both groups. Increased cGMP may reflect the stimulatory effect of peroxides (an activator of guanylate cyclase), because lipid peroxidation is increased in aortae and in plasma in sickle mice. Despite increased vascular cGMP levels in sickle mice, conscious systolic blood pressure is comparable to that of aged-matched controls; sickle mice, however, 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 mice. We conclude that vascular responses are altered in this transgenic sickle 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-independent mechanisms of vasodilatation in this transgenic sickle mouse. Destabilization of the vasoactive balance in the sickle vasculature by clinically relevant states may predispose to vasoocclusive disease.
authors.affiliation: Nephrology, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA..
authors.forename: K A
authors.initials: KA
authors.lastname: Nath
authors.forename: V
authors.initials: V
authors.lastname: Shah
authors.forename: J J
authors.initials: JJ
authors.lastname: Haggard
authors.forename: A J
authors.initials: AJ
authors.lastname: Croatt
authors.forename: L A
authors.initials: LA
authors.lastname: Smith
authors.forename: R P
authors.initials: RP
authors.lastname: Hebbel
authors.forename: Z S
authors.initials: ZS
authors.lastname: Katusic
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001011:Aorta / Q000502:physiology / Q000503:physiopathology; D001323:Autoantibodies / Q000235:genetics; D001794:Blood Pressure; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology; D005914:Globins / Q000172:deficiency / Q000235:genetics*; D006451:Hemoglobin, Sickle / Q000235:genetics* / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D010208:Papaverine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D001323:Autoantibodies; D006451:Hemoglobin, Sickle; D009566:Nitrates; D009573:Nitrites; D000001:Calcimycin; D005914:Globins; D010208:Papaverine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006152:Cyclic GMP