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Comparative Study
. 2008 Oct;35(10):1156-63.
doi: 10.1111/j.1440-1681.2008.04984.x. Epub 2008 Jun 18.

Vascular dysfunction in the alpha-galactosidase A-knockout mouse is an endothelial cell-, plasma membrane-based defect

James L Park  1 , Steven E Whitesall, Louis G D'Alecy, Liming Shu, James A Shayman
Affiliations
Comparative Study

Vascular dysfunction in the alpha-galactosidase A-knockout mouse is an endothelial cell-, plasma membrane-based defect

James L Park et al. Clin Exp Pharmacol Physiol. 2008 Oct.

Abstract

Fabry disease results from an X-linked mutation in the lysosomal alpha-galactosidase A (Gla) gene. Defective Gla results in multi-organ accumulation of neutral glycosphingolipids (GSLs), especially in the vascular endothelium, with the major GSL accumulated being globotriaosylceramide (Gb3). Excessive endothelial Gb3 accumulation is associated with increased thrombosis, atherogenesis and endothelial dysfunction. However, the mechanism(s) by which endothelial dysfunction occurs is unclear. The purpose of the present study was to further characterize the vasculopathy associated with a murine model of Fabry disease. Vascular reactivity was performed in vessels from wild-type (Gla(+/0)) and Gla-knockout (Gla(-/0)) mice. Conscious blood pressure and heart rate were measured in Gla(+/0) and Gla(-/0) mice by telemetry. The present study demonstrates that vascular smooth muscle (VSM) contractions to phenylephrine and serotonin, but not to U46619, were blunted in Gla(-/0) mice. Endothelium-dependent contraction and receptor-mediated endothelium-dependent relaxation to acetylcholine were significantly attenuated in vessels from Gla(-/0) mice. However, receptor-independent endothelium-dependent relaxation to the calcium ionophore ionomycin remained intact in vessels from Gla(-/0) mice. Furthermore, VSM reactivity was normal in aortas from Gla(-/0) mice in the absence of endothelium. These changes in vascular function were observed without changes in whole-animal blood pressure or heart rate. These results suggest that the vasculopathy associated with Fabry disease is localized to the endothelium, despite the accumulation of GSLs throughout the vasculature.

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Figures

Figure 1
Figure 1
a) Conscious diastolic, b) systolic, and c) mean arterial, blood pressures (mmHg) measured during a 28-hour light-dark cycle by telemetry in wildtype (Gla +/0) or Gla knockout (Gla -/0) mice. p>0.05 by two-way ANOVA.
Figure 2
Figure 2
a) Heart rate (beats/min), and calculated myocardial oxygen consumption (mVO2) or b) Rate-Pressure Product obtained from measurements derived from a telemetric blood pressure transducer. p>0.05 by two-way ANOVA.
Figure 3
Figure 3
Phenylephrine (PE)-mediated vascular contraction in endothelium-intact mouse aortic rings from wildtype (Gla +/0) or Gla knockout (Gla -/0) mice a) alone without any pharmacological intervention, b) in the presence of 10-4 mol/L Nω-nitro-l-arginine (LNNA), or c) with endothelium denuded. Data are expressed as a percentage of the contraction elicited by a 100 mmol/L KCl-containing physiological salt solution. * = p<0.05 compared to Gla +/0 by two-way ANOVA followed by Bonferonni post hoc test.
Figure 4
Figure 4
Serotonin (5HT)-mediated vascular contraction in endothelium-intact mouse aortic rings from wildtype (Gla +/0) or Gla knockout (Gla -/0) mice a) alone without any pharmacological intervention, b) in the presence of 10-4 mol/L Nω-nitro-l-arginine (LNNA), or c) with endothelium denuded. Data are expressed as a percentage of the contraction elicited by a 100 mmol/L KCl-containing physiological salt solution. * = p<0.05 compared to Gla +/0 by two-way ANOVA followed by Bonferonni post hoc test.
Figure 5
Figure 5
The thromboxane A2/prostaglandin H2 (TP) receptor agonist, U46619, mediated vascular contraction in endothelium-intact mouse aortic rings from wildtype (Gla +/0) or Gla knockout (Gla -/0) mice a) alone without any pharmacological intervention, b) in the presence of 10-4 mol/L Nω-nitro-l-arginine (LNNA), or c) with endothelium denuded. Data are expressed as a percentage of the contraction elicited by a 100 mmol/L KCl-containing physiological salt solution. * = p<0.05 compared to Gla +/0 by two-way ANOVA followed by Bonferonni post hoc test.
Figure 6
Figure 6
Endothelium-dependent contraction mediated by 10-5 mol/L acetylcholine (Ach) in endothelium-intact and endothelium-denuded (-ENDO) mouse carotid artery rings from wildtype (Gla +/0) or Gla knockout (Gla -/0) mice in the presence of 3 × 10-4 mol/L Nω-nitro-l-arginine (LNNA). * = p<0.05 compared to Gla +/0 and † = p<0.05 compared to Gla +/0 –ENDO by one-way ANOVA; n=5 in each group.
Figure 7
Figure 7
Acetylcholine (Ach)-mediated endothelium-dependent relaxation in endothelium-intact mouse aortic rings from wildtype (Gla +/0) or Gla knockout (Gla -/0) mice pre-contracted with an EC80 concentration of PE a) alone without any pharmacological intervention, b) in the presence of 10-4 mol/L Nω-nitro-l-arginine (LNNA), or c) with endothelium denuded. Data are expressed as a percentage of the contraction elicited by PE EC80. * = p<0.05 compared to Gla +/0 by two-way ANOVA followed by Bonferonni post hoc test.
Figure 8
Figure 8
Ionomycin-induced eNOS-dependent relaxation in endothelium-intact mouse aortic rings from wildtype (Gla +/0) or Gla knockout (Gla -/0) mice pre-contracted with an EC80 concentration of PE a) alone without any pharmacological intervention or b) in the presence of 10-4 mol/L Nω-nitro-l-arginine (LNNA). Data are expressed as a percentage of the contraction elicited by PE EC80. p>0.05 by two-way ANOVA in all figures.
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References

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