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

K. A. Nath, V. Shah, J. J. Haggard, A. J. Croatt, L. A. Smith, R. P. Hebbel, Z. S. Katusic

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

We investigated a transgenic mouse model of sickle cell disease, homozygous for deletion of mouse β-globin and containing transgenes for human β(S) and β(S-antilles) globins linked to the transgene for human α-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.

Original languageEnglish (US)
Pages (from-to)R1949-R1955
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume279
Issue number6 48-6
DOIs
StatePublished - Jan 1 2000

Keywords

  • Cellular redox
  • Cyclic guanosine 5'-monophosphate
  • Peroxide
  • Vasculature

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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